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1
Abang Hamdani, Dayang Hanim Alysha, Ilyanie Hj. Yaacob, and Ida Muryany Md Yasin. "Isolation and characterisation of probiotic lactic acid bacteria from Malaysian fermented shrimp product pekasam senek." International Food Research Journal 31, no. 5 (2024): 1240–52. https://doi.org/10.47836/ifrj.31.5.13.
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Lactic acid bacteria (LAB) from fermented foods have been proven as able to hinder the growth and activities of some foodborne pathogens. The present work thus aimed to isolate and characterise the potential LAB isolated from Malaysian fermented shrimp, pekasam senek (PS). Twelve isolates were obtained and molecularly identified via 16S rRNA gene sequencing, followed by acid and bile salt tolerance assessment, and cholesterol-lowering activity evaluation. The isolates showed satisfactory tolerance in a harsh acidic condition of pH 3.0; ten isolates (PS13, PS14, PS16, PS17, PS20, PS24, PS26, PS27, PS31, and PS33) exhibited over 90% of acid tolerance, while isolate PS22 exhibited 85.37% of acid tolerance, and isolate PS15 exhibited 75.73% of acid tolerance. For bile salts tolerance, nine isolates (PS13, PS14, PS15, PS16, PS17, PS24, PS27, PS31, and PS33) demonstrated survival rates ranging from 50 to 95% after 6 h of exposure to 0.3% bile salts. Despite showing a low tolerance to bile salt in comparison to the control, isolates PS20, PS22, and PS27 were still growing. The strains were identified as Lactiplantibacillus plantarum (PS13, PS15, PS17, PS20, PS24, PS31, and PS33), Bacillus cereus (PS14, and PS16), and Bacillus sp. (PS22, PS26, and PS27), using 16S rRNA gene sequencing. Lastly, PS24 and PS31 showed the highest cholesterol-lowering activity, with reductions of 80.50 and 80.19%, respectively. Meanwhile, PS13, PS14, PS16, PS17, PS20, PS26, PS27, and PS33 showed cholesterol-lowering activity of above 70%, and PS22 showed only 50.55% reduction. Each strain showed characteristics that influenced its ability to survive in acidic conditions, bile salts, and reduce cholesterol levels. These results proved that the isolates could have good properties as probiotics with positive cholesterol-lowering activity.
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Metzger, S., M. Odermatt, Z. Szendrő, et al. "Comparison of carcass traits and meat quality of Hyplus hybrid, purebred Pannon White rabbits and their crossbreds." Archives Animal Breeding 49, no. 4 (2006): 389–99. http://dx.doi.org/10.5194/aab-49-389-2006.
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Abstract. The aim of the experiment was to compare the weight gain, carcass traits and meat quality of Hyplus hybrid (HH, offspring of Hyplus PS59 bucks and Hyplus PS19 does, n = 77), purebred Pannon White rabbits (PP, offspring of Pannon White bucks and Pannon White does, n = 84) and their crossbreds (PH: offspring of Pannon White bucks and Hyplus PS19 does, n = 97; HP: offspring of Hyplus PS59 bucks and Pannon White does, n = 79). Pannon White rabbits are selected for body weight gain and for carcass traits by computerised tomography (CT), while Hyplus PS19 females and Hyplus PS59 males are selected on prolificacy and body weight gain, respectively. Rabbits of HP genotype had the highest while those of PP genotype the lowest body weight gain (38.9 and 36.6 g/day, respectively; P<0.05). Pannon White breed had an advantageous influence on dressing out percentage (PP: 58.0%; PH: 58.7%; HP: 57.7%; HH: 57.6%; P<0.001) and on the weight of the m. Longissimus dorsi (PP: 152 g; PH: 143 g; HP: 137 g; HH: 136 g; P<0.001). The fat content of the carcass was lower in the offspring of the Hyplus PS59 bucks (1.15, 1.16, 0.89 and 0.85% for PP, PH, HP and HH rabbits, respectively; P<0.001). Significant differences were found between the meat samples of progenies of purebred Pannon White and the hybrid terminal cross rabbits in the moisture and fat content of hindleg meat (moisture content: PP: 75.5%, HH: 76.1%, P<0.05; fat content: PP: 2.38%, HH: 1.46%; P<0.001). From the view point of dressing out percentage and the volume of the m. Longissimus dorsi the usage of Pannon White genotype is advantageous. Dressing out percentage of the offspring of the early-matured Hyplus PS19 does and Pannon White bucks selected with the help of computerised tomography is remarkable.
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Świątek, Piotr, Katarzyna Gębczak, Tomasz Gębarowski, and Rafal Urniaz. "Biological Evaluation and Molecular Docking Studies of Dimethylpyridine Derivatives." Molecules 24, no. 6 (2019): 1093. http://dx.doi.org/10.3390/molecules24061093.
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Cyclooxygenase inhibitors as anti-inflammatory agents can be used in chemoprevention. Many in vitro and in vivo studies on human and animal models have explained the mechanisms of the chemopreventive effect of COX inhibitors such as: induction of apoptosis, inhibition of neoplasia, angiogenesis suppression, induction of cell cycle inhibition and inhibition of the expression of peroxisome proliferator-activated receptors. Here, biological evaluation of twelve different Schiff base derivatives of N-(2-hydrazine-2-oxoethyl)-4,6-dimethyl-2-sulfanylpyridine- 3-carboxamide are presented. Their in vitro anti-COX-1/COX-2, antioxidant and anticancer activities were studied. The molecular docking study was performed in order to understand the binding interaction of compounds in the active site of cyclooxygenases. Compounds PS18 and PS33 showed a significant inhibitory activity on COX-1 at lower concentrations compared to meloxicam and piroxicam. The IC50 of COX-1 of these compounds was 57.3 µM for PS18 and 51.8 µM for PS33. Out of the tested compounds, the highest therapeutic index was demonstrated by PS18, PS19, PS33, PS40 and PS41. Lower molar concentrations of these compounds inhibit the growth of cancer cells while not inhibiting the healthy cells. Compounds PS18, PS19 and PS33 simultaneously demonstrated a statistically-significant inhibition of COX-1 or COX-2. This opens up the possibility of applying these compounds in the chemoprevention of cancer.
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Yang, Joshua, Weijun Ou, Nataraj Jagadeesan, et al. "The Effects of a Blood–Brain Barrier Penetrating Erythropoietin in a Mouse Model of Tauopathy." Pharmaceuticals 16, no. 4 (2023): 558. http://dx.doi.org/10.3390/ph16040558.
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Erythropoietin (EPO), a hematopoietic neurotrophin, is a potential therapeutic for Alzheimer’s disease (AD) but has limited blood–brain barrier (BBB) permeability. EPO fused to a chimeric transferrin receptor monoclonal antibody (cTfRMAb) enters the brain via TfR-mediated transcytosis across the BBB. We previously showed that cTfRMAb-EPO is protective in a mouse model of amyloidosis, but its effects on tauopathy are not known. Given that amyloid and tau pathology are characteristics of AD, the effects of cTfRMAb-EPO were studied in a tauopathy mouse model (PS19). Six-month-old PS19 mice were injected intraperitoneally with either saline (PS19-Saline; n = 9) or cTfRMAb-EPO (PS19-cTfRMAb-EPO, 10 mg/kg; n = 10); every two or three days on alternate weeks for 8 weeks. Age-matched, saline-treated, wildtype littermates (WT-Saline; n = 12) were injected using the same protocol. After 8 weeks, locomotion, hyperactivity, and anxiety were assessed via the open-field test, and brains were harvested and sectioned. Cerebral cortex, hippocampus, amygdala, and entorhinal cortex sections were analyzed for phospho-tau (AT8) and microgliosis (Iba1). Hippocampal cellular density (H&E) was also assessed. PS19-Saline mice were hyperactive and less anxious compared to WT-Saline mice, and these behavioral phenotypes were significantly reduced in the PS19-cTfRMAb-EPO mice compared to the PS19-Saline mice. cTfRMAb-EPO significantly reduced AT8 load by ≥50% in all of the brain regions analyzed and microgliosis in the entorhinal cortex and amygdala compared to the PS19-Saline mice. Hippocampal pyramidal and granule cell layer density did not differ significantly between the PS19-cTfRMAb-EPO and PS19-Saline mice. This proof-of-concept study demonstrates the therapeutic effects of the BBB-penetrating cTfRMAb-EPO in PS19 mice.
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Kam, Korey, Kenny Vetter, and Andrew Varga. "0274 Effect of aging on sleep architecture including a novel REM Behavior Disorder phenotype in the PS19 mouse model of tauopathy and effect of a dual orexin receptor antagonist." Sleep 45, Supplement_1 (2022): A123—A124. http://dx.doi.org/10.1093/sleep/zsac079.272.
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Abstract Introduction This project examines changes to sleep micro-architecture with aging in the PS19 (MAPT P301S) model of tauopathy and response to a dual orexin receptor antagonist (DORA-12) in aged PS19 mice. Methods 24-hour video PSG recordings occurred in 28 PS19 mice and 22 littermate controls at 2-3 months (young) and 10-14 months (old). Results Spindle density significantly deceased as a function of both advanced age and PS19 genotype without interaction. We observed a significant interaction between age and genotype on slow oscillation (SO) density such that SO density was higher in young PS19 lower in old PS19 mice vs controls without main effects of age or genotype. Phase amplitude coupling of spindles to detected SO events was significantly decreased as a function of age with a trend toward an age/genotype interaction such that the reduction in coupling was greater with aging in PS19 mice vs controls. We observed unexpected dream enactment during REM in 3 of 11 old PS19 but not in young PS19 mice or control mice at any age. Normalized cumulative EMG area during REM sleep, cumulative duration of elevated EMG in REM, and %REM w/o atonia were all significantly increased in mice displaying dream enactment.Old PS19 mice were also video-PSG recorded for 24 hours while receiving 100 mg/kg DORA-12 vs vehicle control orally twice daily. DORA-12 resulted in significant reduction in latency to persistent NREM and REM sleep, and significant increases in spindle density and SO density, without significant difference in spindle-SO coupling. While we did not observe significant differences in dream enactment measures with DORA-12 due to low sample size, all 3 mice with dream enactment displayed decreases in normalized EMG amplitude in REM and %REM with EMG bursts with DORA-12 ranging from 10 to 60%. Conclusion Given the importance of spindles, SO’s, and their coupling on cognitive processes, these observations can motivate further evaluation of DORA’s toward such cognitive processes in neurodegenerative models as well as effect of DORA’s on RBD phenotypes. Support (If Any)
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Takaichi, Yuta, James K. Chambers, Yasuhisa Ano, Akihiko Takashima, Hiroyuki Nakayama та Kazuyuki Uchida. "Deposition of Phosphorylated α-Synuclein and Activation of GSK-3β and PP2A in the PS19 Mouse Model of Tauopathy". Journal of Neuropathology & Experimental Neurology 80, № 8 (2021): 731–40. http://dx.doi.org/10.1093/jnen/nlab054.
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Abstract The simultaneous accumulation of multiple pathological proteins, such as hyperphosphorylated tau (hp-tau) and phosphorylated α-synuclein (p-αSyn), has been reported in the brains of patients with various neurodegenerative diseases. We previously demonstrated that hp-tau-dependent p-αSyn accumulation was associated with the activation of GSK-3β in the brains of P301L tau transgenic mice. To confirm the effects of another mutant tau on p-αSyn accumulation in vivo, we herein examined the brains of PS19 mice that overexpress human P301S mutant tau. Immunohistochemically, hp-tau and p-αSyn aggregates were detected in the same neuronal cells in the cerebrum and brain stem of aged PS19 mice. A semiquantitative analysis showed a positive correlation between hp-tau and p-αSyn accumulation. Furthermore, an activated form of GSK-3β was detected within cells containing both hp-tau and p-αSyn aggregates in PS19 mice. Western blotting showed a decrease in inactivated PP2A levels in PS19 mice. The present results suggest that the overexpression of human P301S mutant tau induces p-αSyn accumulation that is accompanied by not only GSK-3β, but also PP2A activation in PS19 mice, and highlight the synergic effects between tau and αSyn in the pathophysiology of neurodegenerative diseases that show the codeposition of tau and αSyn.
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Gallagher, Evan, Shihong Li, Hsiaoju Lee, et al. "Noninvasive Detection of Oxidative Stress in a Mouse Model of 4R Tauopathy via Positron Emission Tomography with [18F]ROStrace." International Journal of Molecular Sciences 26, no. 5 (2025): 1845. https://doi.org/10.3390/ijms26051845.
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Oxidative stress, defined as the excessive production of reactive oxygen species (ROS), is a crucial factor in the pathogenesis of various neurodegenerative diseases, including the 4-repeat (4R) tauopathies. Collectively, the 4R tauopathies are characterized by the progressive aggregation of tau protein isoforms with four microtubule-binding domains in and around brain cells. The cyclical relationship between oxidative stress and 4R tau aggregation suggests that a means of imaging ROS noninvasively could be a valuable tool for the study and treatment of 4R tauopathy in both humans and animal models. To demonstrate the potential of the ROS-sensitive positron emission tomography (PET) radiotracer [18F]ROStrace as a means of filling this methodological gap, we performed [18F]ROStrace PET imaging on PS19 mice, which exhibit 4R tau aggregation similar to that seen in human 4R tauopathy. Significant increases in [18F]ROStrace signal became detectable in the hippocampus of 6–11-month-old (mo) PS19 animals and spread to the brainstem, midbrain, and thalamus of 11+ mo animals. Additionally, older PS19 mice displayed higher whole-brain average [18F]ROStrace signal compared to age-matched controls (p = 0.042), and tau pathology consistently colocalized with multiple fluorescent indicators of oxidative stress in PS19 brain samples. These results provide novel evidence that 4R tau aggregation is associated with increased oxidative stress in PS19 mouse brain and advance [18F]ROStrace as a noninvasive technology for the detection of oxidative stress in neurodegenerative diseases involving tau pathology.
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Ahmad, Faraz, Hannah Mein, Yu Jing, Hu Zhang, and Ping Liu. "Behavioural Functions and Cerebral Blood Flow in a P301S Tauopathy Mouse Model: A Time-Course Study." International Journal of Molecular Sciences 22, no. 18 (2021): 9727. http://dx.doi.org/10.3390/ijms22189727.
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Tauopathies refer to a group of neurodegenerative diseases with intracellular accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) in neurons and glial cells. PS19 mice bearing the MAPT P301S mutation have been used to mimic human frontotemporal lobar degeneration. The present study was designed to systematically investigate how behavioural functions, resting cerebral blood flow (CBF) and tau pathology change in PS19 mice at 2, 4, 6, 8 and 12 months of age in a single study under one experimental condition, allowing for the cumulative assessment of age- and genotype-dependent changes. PS19 mice displayed hyperactivity and reduced anxiety levels with age, early and persistent spatial working memory deficits and reduced resting neocortical CBF. Immunoblotting and immunohistochemistry revealed age-related increases in phosphorylated tau in the brain of PS19 mice. In conclusion, the present study, for the first time, cumulatively demonstrated the time-course of changes in behavioural functions, resting CBF and tau pathology in a P301S tauopathy mouse model through their developmental span. This information provides further evidence for the utility of this model to study neurodegenerative events associated with tauopathy and tau dysfunction.
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Martin, Shenée C., Kathryn K. Joyce, Kathryn M. Harper, et al. "Evaluating Fatty Acid Amide Hydrolase as a Suitable Target for Sleep Promotion in a Transgenic TauP301S Mouse Model of Neurodegeneration." Pharmaceuticals 17, no. 3 (2024): 319. http://dx.doi.org/10.3390/ph17030319.
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Sleep disruption is an expected component of aging and neurodegenerative conditions, including Alzheimer’s disease (AD). Sleep disruption has been demonstrated as a driver of AD pathology and cognitive decline. Therefore, treatments designed to maintain sleep may be effective in slowing or halting AD progression. However, commonly used sleep aid medications are associated with an increased risk of AD, highlighting the need for sleep aids with novel mechanisms of action. The endocannabinoid system holds promise as a potentially effective and novel sleep-enhancing target. By using pharmacology and genetic knockout strategies, we evaluated fatty acid amide hydrolase (FAAH) as a therapeutic target to improve sleep and halt disease progression in a transgenic Tau P301S (PS19) model of Tauopathy and AD. We have recently shown that PS19 mice exhibit sleep disruption in the form of dark phase hyperarousal as an early symptom that precedes robust Tau pathology and cognitive decline. Acute FAAH inhibition with PF3845 resulted in immediate improvements in sleep behaviors in male and female PS19 mice, supporting FAAH as a potentially suitable sleep-promoting target. Moreover, sustained drug dosing for 5–10 days resulted in maintained improvements in sleep. To evaluate the effect of chronic FAAH inhibition as a possible therapeutic strategy, we generated FAAH−/− PS19 mice models. Counter to our expectations, FAAH knockout did not protect PS19 mice from progressive sleep loss, neuroinflammation, or cognitive decline. Our results provide support for FAAH as a novel target for sleep-promoting therapies but further indicate that the complete loss of FAAH activity may be detrimental.
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Vetter, Kenny, Ward Pettibone, Rachel Tejiram, Korey Kam, and Andrew Varga. "0200 Effects of Early-Life Sleep Disruption on Spatial Learning, Tau Burden, and Neurodegeneration in the PS19 Mouse Model of Tauopathy." SLEEP 46, Supplement_1 (2023): A89. http://dx.doi.org/10.1093/sleep/zsad077.0200.
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Abstract Introduction Sleep disruption is thought to increase tau hyperphosphorylation and tangle formation. This study aims to identify the impact of chronic early-life sleep disruption on late-life tau burden, neurodegeneration, and spatial memory. Methods Eight-week-old PS19 (MAPT P301S) mice and wildtype littermates were subjected to chronic daily sleep disruption (SD) or allowed to sleep ad libitum (AL) for eight weeks. SD was achieved using an automated physical stimulus every 10 seconds for 18 hours daily between ZT 0 and 18. Spatial memory testing occurred at 6, 8, and 10 months of age using the Barnes maze where latencies to find and enter the escape box were recorded on 4 consecutive days (n: WT AL=22, WT SD=21, PS19 AL=15, PS19 SD=28). Brains were subsequently collected between 10 and 14 months of age and analyzed in a subset. Tau pathology was analyzed with AT8 immunohistochemistry on paraffin sections and quantified by counting tau-positive hippocampal neurons using QuPath software. Neurodegeneration was quantified by measuring the combined area of both the lateral and third ventricles. Results Spatial memory was equivalent among all genotypes and sleep conditions at 6 months. We observed a main effect of PS19 genotype with worse spatial memory at 8 and 10 months. Notably, early life SD imparted a protective effect on spatial memory at 8 and 10 months vs ad lib sleep in PS19 mice with no effect on controls. PS19 mice experiencing early life SD showed no difference in late-life hippocampal tau burden (SD: mean 462 AT8+ neurons (SEM: 268), n=5, AL: 284 AT8+ neurons (SEM: 98), n=5, p=0.56) as well as no difference in total ventricle area (SD: mean 1.2 square mm (SEM: 0.5), n=5, AL: 2.0 square mm (SEM: 0.4), n=5, p=0.26). Conclusion Counter to our initial hypothesis, early-life SD resulted in preservation of late-life spatial memory, without changes to neurodegeneration as measured by ventricle area or changes to tau hyperphosphorylation in the hippocampus. Dissociation of tau burden and memory has been observed in models of immune modulation suggesting further investigation regarding effects of sleep disruption on immune function in the context of neurodegenerative models. Support (if any)
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Drieu, Antoine, Siling Du, Michal Kipnis, et al. "Parenchymal border macrophages regulate tau pathology and tau-mediated neurodegeneration." Life Science Alliance 6, no. 11 (2023): e202302087. http://dx.doi.org/10.26508/lsa.202302087.
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Parenchymal border macrophages (PBMs) reside close to the central nervous system parenchyma and regulate CSF flow dynamics. We recently demonstrated that PBMs provide a clearance pathway for amyloid-β peptide, which accumulates in the brain in Alzheimer’s disease (AD). Given the emerging role for PBMs in AD, we explored how tau pathology affects the CSF flow and the PBM populations in the PS19 mouse model of tau pathology. We demonstrated a reduction of CSF flow, and an increase in an MHCII+PBM subpopulation in PS19 mice compared with WT littermates. Consequently, we asked whether PBM dysfunction could exacerbate tau pathology and tau-mediated neurodegeneration. Pharmacological depletion of PBMs in PS19 mice led to an increase in tau pathology and tau-dependent neurodegeneration, which was independent of gliosis or aquaporin-4 depolarization, essential for the CSF-ISF exchange. Together, our results identify PBMs as novel cellular regulators of tau pathology and tau-mediated neurodegeneration.
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Arroyo Loranca, Raquel Gabriela, Crisalejandra Rivera Pérez, Luis Hernández Adame, Ariel Arturo Cruz Villacorta, José Luis Rodríguez López, and Norma Yolanda Hernández Saavedra. "Effect of ion and protein concentration of Ps19, a shell protein from Pteria sterna, on calcium carbonate polymorph." Biotecnia 25, no. 2 (2023): 136–45. http://dx.doi.org/10.18633/biotecnia.v25i2.1885.
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Calcium carbonate is present in many biological structures such as bivalve shell, which is composed mainly of two CaCO3 polymorphs: calcite and aragonite. However, exist other forms of calcium carbonate like vaterite and amorphous calcium carbonate (ACC) that are not commonly reported. Polymorph selection is influenced by salt concentration, cofactor ions, and the presence of shell matrix proteins (SMPs) which regulates calcium carbonate deposition, among other factors. In this study, calcium carbonate crystallization in vitro of four different saline solutions at two molarities was evaluated with increased concentrations of the Ps19 protein, an insoluble extracted protein from the shell of Pteria sterna, previously described as a promotor of aragonite platelet crystallization. In vitro crystallizations showed that Ps19 is capable to induce aragonite and calcite deposition in a dose-dependent manner, but also vaterite under ciertan conditions, acting as a promoter and inhibitor of crystallization. The results contribute to understand how Ps19 control precipitation of calcium polymorphs in the growth of the prismatic and nacre layer of the shell of P. sterna.
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Jennings, Michael, James Booker, Amy Addison, Rebecca Egglestone, and Ahilanandan Dushianthan. "Predictors of mortality for blunt trauma patients in intensive care: A retrospective cohort study." F1000Research 12 (October 1, 2024): 974. http://dx.doi.org/10.12688/f1000research.138364.4.
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Background: Major trauma places substantial demand on critical care services, is a leading cause of death in under 40-year-olds and causes significant morbidity and mortality across all age groups. Various factors influence patient outcome and predefining these could allow prognostication. The aim of this study was to identify predictors of mortality from major trauma in intensive care. Methods: This was a retrospective study of adult trauma patients admitted to general intensive care between January 2018 and December 2019. We assessed the impact on mortality of patient demographics, patterns of injury, injury scores (Glasgow Coma Score (GCS), Charlson’s comorbidity index (CCI), Acute Physiology and Health Evaluation II (APACHE II), Injury Severity Score (ISS) and Probability of Survival Score (Ps19)), number of surgeries and mechanism of injury using logistic regression. Results: A total of 414 patients were included with a median age of 54 years (IQR 34–72). Overall mortality was 18.6%. The most common mechanism of injury was traffic collision (46%). Non-survivors were older, had higher ISS scores with lower GCS on admission and probability of survival scores. Factors independently predictive of mortality were increasing age (OR 1.06, p <0.001) and GCS <15 on admission (OR 7.21, p <0.001). Ps19 was the best predictor of mortality (p <0.001 for each score category), with an AUROC of 0.90. Conclusions: The significant mortality predictors were age, fall from <2 metres, injury of head or limbs, GCS <15 and Ps19. Contrary to previous studies CCI and APACHE II did not significantly predict mortality. Although Ps19 was found to be the best current prognostic score, trauma prognostication would benefit from a single validated scoring system incorporating both physiological variables and injury patterns.
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Jennings, Michael, James Booker, Amy Addison, Rebecca Egglestone, and Ahilanandan Dushianthan. "Predictors of mortality for blunt trauma patients in intensive care: A retrospective cohort study." F1000Research 12 (August 12, 2024): 974. http://dx.doi.org/10.12688/f1000research.138364.3.
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Background: Major trauma places substantial demand on critical care services, is a leading cause of death in under 40-year-olds and causes significant morbidity and mortality across all age groups. Various factors influence patient outcome and predefining these could allow prognostication. The aim of this study was to identify predictors of mortality from major trauma in intensive care. Methods: This was a retrospective study of adult trauma patients admitted to general intensive care between January 2018 and December 2019. We assessed the impact on mortality of patient demographics, patterns of injury, injury scores (Glasgow Coma Score (GCS), Charlson’s comorbidity index (CCI), Acute Physiology and Health Evaluation II (APACHE II), Injury Severity Score (ISS) and Probability of Survival Score (Ps19)), number of surgeries and mechanism of injury using logistic regression. Results: A total of 414 patients were included with a median age of 54 years (IQR 34–72). Overall mortality was 18.6%. The most common mechanism of injury was traffic collision (46%). Non-survivors were older, had higher ISS scores with lower GCS on admission and probability of survival scores. Factors independently predictive of mortality were increasing age (OR 1.06, p <0.001) and GCS <15 on admission (OR 7.21, p <0.001). Ps19 was the best predictor of mortality (p <0.001 for each score category), with an AUROC of 0.90. Conclusions: The significant mortality predictors were age, fall from <2 metres, injury of head or limbs, GCS <15 and Ps19. Contrary to previous studies CCI and APACHE II did not significantly predict mortality. Although Ps19 was found to be the best current prognostic score, trauma prognostication would benefit from a single validated scoring system incorporating both physiological variables and injury patterns.
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Jennings, Michael, James Booker, Amy Addison, Rebecca Egglestone, and Ahilanandan Dushianthan. "Predictors of mortality for blunt trauma patients in intensive care: A retrospective cohort study." F1000Research 12 (December 6, 2024): 974. https://doi.org/10.12688/f1000research.138364.5.
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Background Major trauma places substantial demand on critical care services, is a leading cause of death in under 40-year-olds and causes significant morbidity and mortality across all age groups. Various factors influence patient outcome and predefining these could allow prognostication. The aim of this study was to identify predictors of mortality from major trauma in intensive care. Methods This was a retrospective study of adult trauma patients admitted to general intensive care between January 2018 and December 2019. We assessed the impact on mortality of patient demographics, patterns of injury, injury scores (Glasgow Coma Score (GCS), Charlson’s comorbidity index (CCI), Acute Physiology and Health Evaluation II (APACHE II), Injury Severity Score (ISS) and Probability of Survival Score (Ps19)), number of surgeries and mechanism of injury using logistic regression. Results A total of 414 patients were included with a median age of 54 years (IQR 34–72). Overall mortality was 18.6%. The most common mechanism of injury was traffic collision (46%). Non-survivors were older, had higher ISS scores with lower GCS on admission and lower probability of survival scores. Factors independently predictive of mortality were age 70-80 (OR 3.267, p = 0.029), age >80 (OR 27.043, p < 0.001) and GCS < 15 (OR 8.728, p < 0.001). Ps19 was the best predictor of mortality (p <0.001 for each score category), with an AUROC of 0.90. Conclusions The significant mortality predictors were age, fall from <2 metres, injury of head or limbs, GCS <15 and Ps19. Contrary to previous studies, CCI and APACHE II did not significantly predict mortality. Although Ps19 was found to be the best current prognostic score, trauma prognostication would benefit from a single validated scoring system incorporating both physiological variables and injury patterns.
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Jennings, Michael, James Booker, Amy Addison, Rebecca Egglestone, and Ahilanandan Dushianthan. "Predictors of mortality for major trauma patients in intensive care: A retrospective cohort study." F1000Research 12 (August 14, 2023): 974. http://dx.doi.org/10.12688/f1000research.138364.1.
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Background: Major trauma places substantial demand on critical care services, is a leading cause of death in under 40-year-olds and causes significant morbidity and mortality across all age groups. Various factors influence patient outcome and predefining these could allow prognostication. The aim of this study was to identify predictors of mortality from major trauma in intensive care. Methods: This was a retrospective study of adult trauma patients admitted to general intensive care between January 2018 and December 2019. We assessed the impact on mortality of patient demographics, patterns of injury, injury scores (Glasgow Coma Score (GCS), Charlson’s comorbidity index (CCI), Acute Physiology and Health Evaluation II (APACHE II), Injury Severity Score (ISS) and Probability of Survival Score (Ps19)), number of surgeries and mechanism of injury using logistic regression. Results: A total of 414 patients were included with a median age of 54 years (IQR 34–72). Overall mortality was 18.6%. The most common mechanism of injury was traffic collision (46%). Non-survivors were older, had higher ISS scores with lower GCS on admission and probability of survival scores. Factors independently predictive of mortality were increasing age (OR 1.06, p <0.001) and GCS <15 on admission (OR 7.21, p <0.001). Ps19 was the best predictor of mortality (p <0.001 for each score category), with an AUROC of 0.90. Conclusions: The significant mortality predictors were age, fall from <2 metres, injury of head or limbs, GCS <15 and Ps19. Contrary to previous studies CCI and APACHE II did not significantly predict mortality. Although Ps19 was found to be the best current prognostic score, trauma prognostication would benefit from a single validated scoring system incorporating both physiological variables and injury patterns.
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Mein, Hannah, Yu Jing, Faraz Ahmad, Hu Zhang, and Ping Liu. "Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study." International Journal of Molecular Sciences 23, no. 11 (2022): 6039. http://dx.doi.org/10.3390/ijms23116039.
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Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the MAPT P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system.
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Kam, K., M. Vetter, N. Berryman, and A. Varga. "0418 Effect of Acute Administration of DORA-12 on Sleep Impairment in the Aged PS19 Mouse Model of Tauopathy." Sleep 43, Supplement_1 (2020): A160. http://dx.doi.org/10.1093/sleep/zsaa056.415.
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Abstract Introduction Aged PS19 mice (MAPT P301S), a mouse model of tauopathy and neurodegeneration, display reduced NREM and REM sleep starting around 8-9 months before death around 12 months. Here, we tested the acute effect of a dual orexin receptor antagonist (DORA-12) on sleep in 11 mice (5 male, 6 female) at 10.3±1.8 months. Methods Two consecutive 24-hour recordings (12/12hr L:D cycle) were scored semi-automatically for non-REM sleep, REM sleep, and wake in mice implanted with EEG/EMG. Mice were treated with either vehicle (day 1) or 100mg/kg of DORA-12 (day 2) by oral gavage at both ZT0 and ZT9. Results After the first dose at ZT0, both latency to the first NREM sleep episode (paired t-test p=0.002) and to the first REM sleep episode (paired t-test p=0.005) was significantly shorter with DORA-12 (NREM: 20.8±17.8 min.; REM: 23.5±21.2 min.) compared to vehicle (NREM: 49.2±22.3 min.; REM: 127.0±93.3 min.). There was no difference in NREM or REM sleep latency observed after the second dose at ZT9. DORA-12 treatment increased NREM duration across the 24hr period (DORA-12: 664±52 min.; Veh: 601±54 min., paired t-test p=0.007) and also after the 2nd dose (DORA-12: 311±65 min.; Veh: 263±84 min., paired t-test p=0.009). DORA-12 treatment also increased REM duration across 24hrs (DORA-12: 61±30 min.; Veh: 48±29 min., paired t-test p=0.014) but not after the 2nd dose alone (DORA-12: 22±14 min.; Veh: 20±15 min., paired t-test p=0.388). Notably in both vehicle and DORA-12 conditions, we observed apparent dream enactment behavior including mastication, paw grasp, and fore limb extension during REM in 3 of 11 PS19 mice (all male), not typically observed in younger PS19 or age-matched non-transgenic mice, suggestive of a possible REM behavior disorder (RBD) phenotype. Wake-like behaviors occurred during theta-dominant EEG but with an EMG amplitude &gt;4SD the preceding NREM sleep baseline for at least &gt; 1sec. Conclusion In aged PS19 mice, DORA-12 was found to decrease the latency to NREM and REM after the first dose while also increasing NREM and REM duration across the entire 24hr recording period. We also capture a heretofore undescribed RBD-like phenotype in aged PS19 tauopathy mice. Support Merck MISP
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Harris, Christopher J., Nora E. Gray, Maya Caruso, Marguex Hunter, Martina Ralle, and Joseph F. Quinn. "Copper Modulation and Memory Impairment due to Hippocampal Tau Pathology." Journal of Alzheimer's Disease 78, no. 1 (2020): 49–60. http://dx.doi.org/10.3233/jad-200002.
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Background: Environmental copper has been implicated in the pathogenesis of Alzheimer’s disease based on evidence that: 1) brain copper levels increase with age, 2) copper promotes misfolding and toxicity of amyloid-β in vitro, 3) copper-modulating interventions reduce amyloid pathology in animal models. However, the effect of copper upon non-amyloid Alzheimer’s pathology is relatively under-explored. Objective: To determine if modulation of brain copper level affects brain tau pathology and/or associated cognitive impairment. Methods: We tested the hypothesis that brain copper modulates tau pathology by manipulating brain levels of copper in the PS19 transgenic mouse model of tau pathology. We treated PS19 and wild-type mice with oral zinc acetate, an established therapy for long term control of excess brain copper, and examined treatment effects upon brain copper, brain tau, NFT-like pathology, and spatial memory. We treated a second cohort of mice with exogenous dietary copper in order to evaluate whether excess environmental copper promotes brain tau pathology. Results: Copper-lowering with oral zinc attenuated spatial memory impairment in female but not male PS19 mice, without a significant effect upon tau pathology. Copper loading increased brain copper, but did not have an effect on brain tau pathology or spatial memory function. Conclusion: These findings suggest that a strategy to lower brain copper may be viable for symptomatic benefit in the setting of tau neuropathology, but unlikely to have robust effects on the underlying pathology. These findings are consistent with dietary or other exogenous copper being unlikely to promote tau pathology.
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Sanchez, Jessica Ramirez, Samual Marsh, Laura McIntyre, Hayk Davtyan, Craig Walsh, and Mathew Blurton-Jones. "Cytotoxic T cells infiltrate the brain and interact with microglia to reduce Alzheimer’s Disease pathogenesis." Journal of Immunology 204, no. 1_Supplement (2020): 64.4. http://dx.doi.org/10.4049/jimmunol.204.supp.64.4.
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Abstract The role of the adaptive immune system, specifically T cells, remains poorly understood in Alzheimer’s disease (AD) pathogenesis research. Our lab generated an immune-deficient mouse model of AD (RAG2ɣc−/−5xfAD) which showed a dramatic increase in amyloid plaque load, an activated microglial neuroinflammatory state, and a decrease in the ability of microglia to phagocytose beta-amyloid. Restoration of adaptive immunity via bone marrow transplantation led to a corresponding decrease in amyloid plaques, indicating a fundamental role for adaptive immunity in AD pathology. Further adoptive transfers into these aged immune-deficient mice showed a significant increase in memory CD8+ T cells and microglia in the RAG2ɣc−/−5xfAD brain parenchyma via flow cytometry. Interestingly, T cells were observed adjacent to plaque-associated microglia in these brains via Immunohistochemistry. To determine whether T cell infiltration also occurs in immune-intact AD mice, flow cytometry was conducted on 5xfAD mice that develop amyloid plaques, PS19 mice that develop neurofibrillary tangles, PS19-5xfAD bigenic mouse model, and wild-type mice. This analysis validated the immune-deficient observations, demonstrating a significant increase in memory CD8+ T cells in 5xfAD mice brains but also revealed a further significant increase in the bigenic PS19-5xfAD model. Therefore, I hypothesize that cytotoxic T cells respond to the inflammatory AD environment by infiltrating the brain and directly interacting with microglia to decrease amyloid plaques. My initial data clearly demonstrate that further examination of the crosstalk between adaptive and innate immunity is needed to determine the mechanisms by which T cells influence AD pathogenesis.
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Hurst, L., M. Stafford, R. Cooper, M. Richards, and D. Kuh. "PS19 Lifetime Socioeconomic Inequalities in Physical and Cognitive Ageing." Journal of Epidemiology and Community Health 66, Suppl 1 (2012): A45.3—A46. http://dx.doi.org/10.1136/jech-2012-201753.118.
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Asada, Takashi, Hiroyuki Kato, and Kazuaki Sasaki. "PS19 Phase field analysis of superelasticity in shape memory alloy." Proceedings of the Materials and Mechanics Conference 2009 (2009): 470–72. http://dx.doi.org/10.1299/jsmemm.2009.470.
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Branch, W. D., C. K. Kvien, and A. K. Culbreath. "Naturally and Artificially Drought-Induced Small-Plants within the Pure-Line Runner-Type Peanut Cultivar ‘Georgia-10T’." Peanut Science 46, no. 2 (2019): 198–202. http://dx.doi.org/10.3146/ps19-1.1.
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ABSTRACT During 2011 at Tifton and Plains, GA, there was an early-season drought stress period during May and June. A few drought-tolerant plants were identified and tagged which appeared green and turgid amongst otherwise dry and severely-wilted plants within the pure-line, runner-type peanut (Arachis hypogaea L.) cultivar, ‘Georgia-10T'. Pod and seeds were harvested from these drought-tolerant individual plant selections (IPS) for increase and testing. During autumn and winter of 2014 to 2015, a greenhouse drought study was utilized to test these IPS's compared to the parental check cultivar. Green and turgid plants were identified within the same check cultivar after exposing the plants to an early-season two-wk drought stress period at 60 and 90 d after planting. Seed from IPS of naturally occurring and artificially drought-induced plants produced similar normal and small-plants. Replicated preliminary yield tests were conducted during 2017 to compare progeny rows from these IPS's to the check cultivar, Georgia-10T. Field trial data indicated that the smaller-plants produced from early-season drought stress had significantly reduced yield, grade, pod size, and seed size as compared to larger plant selections and Georgia-10T parental cultivar. In a greenhouse study conducted during autumn and winter of 2017 to 2018, these small plants had significantly shorter internode length and mainstem height compared to the same small plants treated with gibberellic acid (GA3) which were taller and had longer internode lengths after one and two months. Small plants resulted from artificially and naturally occurring early-season drought-induced stress within the pure-line runner-type peanut cultivar, Georgia-10T, were caused by lack of GA3. The normal and small-plants each have bred true-to-type following several self-generations. The ramification of these findings suggest the importance of early-season irrigation, especially for seed production of peanut cultivars to avoid subsequent development of low-yielding, small-plants induced by drought-stress.
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Pegues, K. D., R. S. Tubbs, G. H. Harris, and W. S. Monfort. "Effect of Calcium Source and Irrigation on Soil and Plant Cation Concentrations in Peanut (Arachis hypogaea L.)." Peanut Science 46, no. 2 (2019): 206–12. http://dx.doi.org/10.3146/ps19-10.1.
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ABSTRACT Calcium improves seed formation and development of peanut kernels. Two primary sources of Ca fertilization in peanut are gypsum (CaSO4) and dolomitic lime (CaMg[CO3]2+CaCO3). Objectives of this research are to determine whether gypsum, lime, or application of both influences pH, extractable [Ca], [Mg], and [K] in the soil along with nutrient absorption, yield, and total sound mature kernels (TSMK) in peanut pods in irrigated compared to non-irrigated conditions. Experiments conducted in Tifton, GA in 2016 and 2017 evaluated Ca treatments with no supplemental Ca fertilizer, gypsum (330 kg Ca/ha) applied at first bloom, lime (897 kg Ca/ha) applied at planting, and lime (897 kg Ca/ha) applied at planting followed by gypsum (330 kg Ca/ha) applied at first bloom. Irrigating increased soil pH, [Ca] and [Mg] in pods, plus yield and TSMK of peanut. Irrigation also decreased [K] in pods, which was correlated with increased pod [Ca]. Soil pH and soil [Ca], [Mg], and [K] were influenced by fertilizer treatment, along with [Ca] and [Mg] in pods. Applications of lime increased pH and soil [Ca]. Lime also increased soil [Mg] when applied alone, but not when gypsum was also included. Application of gypsum reduced soil [Mg] when applied alone, but not when lime was included. The inclusion of both lime and gypsum reduced soil [K] compared to no application. These results display the competition of cations in soil. In peanut pods, using lime and gypsum increased [Ca] compared to no application, or only lime. However, when only gypsum was used, it reduced [Mg] in pods compared to a lime application or no fertilization. Although Ca fertilization did not affect yield, TSMK was greater when lime followed by gypsum were applied in sequence than where neither were applied in 2016. It is important to realize that applications of Ca can also influence concentrations of other cations important for growth. Peanut growers are encouraged to conduct soil tests to ensure soil [Mg] is not deficient or borderline before choosing to apply gypsum, and may require a supplemental Mg fertilizer if dolomitic lime was not applied.
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Branch, W. D., S. P. Tallury, J. P. Clevenger, B. M. Schwartz, and W. W. Hanna. "Inheritance of a Novel Heterozygous Peanut Mutant, 5-Small Leaflet." Peanut Science 47, no. 1 (2020): 33–37. http://dx.doi.org/10.3146/ps19-11.1.
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ABSTRACT An unusual 5-Small Leaflet mutant plant was found within the ‘Georgia Green' runner-type peanut (Arachis hypogaea L.) cultivar. Subsequent selfing has not established a true-breeding 5-Small Leaflet genotype. It continues to segregate normal and 5-Small Leaflet plants but with a reduced number of normal leaf plants upon selection for 5-Small Leaflet phenotypes after several self-generations. F1, F2, F3, and F4 data suggests that the 5-Small Leaflet trait is dominant or possibly pseudo-dominant. Likewise, the 5-Small Leaflet mutant can only be used as a pollen parent in crosses, and it has approximately a 1:1 ratio of elongated to normal stigmas, respectively, on individual plants. This is an example of a novel heterozygous peanut mutant plant found within the cultivated allotetraploid peanut.
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Bennett, R. S. "Growth Chamber Assay for Evaluating Resistance to Athelia rolfsii." Peanut Science 47, no. 1 (2020): 25–32. http://dx.doi.org/10.3146/ps19-12.1.
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ABSTRACT Planting resistant cultivars is most sustainable method for managing Athelia rolfsii (= Sclerotium rolfsii), one of the most damaging pathogens of peanut worldwide. However, evaluating germplasm for resistance in the field can be complicated by unfavorable environmental conditions, uneven distribution of sclerotia in soil, and difficulty in growing non-standard peanut genotypes such as wild species. Thus, a growth-chamber assay was used to screen for resistance to A. rolfsii in the laboratory. Thirteen peanut genotypes were used to test the assay: cultivars Georgia-03L, Georgia-12Y, Florida-07, Georgia-07W, Tamrun OL02, FloRun ‘107′, Georgia-06G, and U.S. mini-core accessions CC038 (PI 493581), CC041 (PI 493631), CC068 (PI 493880), CC384 (PI 155107), CC650 (PI 478819), and CC787 (PI 429420). Lesion length, as well as length of visible mycelium, on the main stem and a side stem were recorded at 4, 7, 10, and 13 days after inoculation. In general, patterns of lesion and mycelium growth were similar. The most resistant genotypes, Georgia-03L and CC650, had the smallest lesions and least mycelium growth. However, Georgia-12Y, one of the most resistant cultivars available today, appeared less resistant than Georgia-03L in the assay. Other commercial cultivars were intermediate in lesion and mycelium lengths. The most susceptible entries were CC038, CC041, and CC787. Despite limitations in discriminating among genotypes with intermediate resistance to A. rolfsii, these assays may be useful for pre-screening germplasm to identify physiologically resistant and highly susceptible entries, as well as for screening Arachis species that are difficult to grow in the field.
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Carter, O. W., and E. P. Prostko. "The Effect of Picloram Plus 2,4-Dichlorphenoxyacetic Acid on Peanut Growth and Yield." Peanut Science 47, no. 2 (2020): 111–14. http://dx.doi.org/10.3146/ps19-14.1.
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ABSTRACT Picloram (4-amino-3,5,6-trichloropicolinic acid) injury, in the form of leaf roll, is often observed in peanut fields due to short crop rotations, contaminated irrigation water, treated hay, and contaminated livestock waste. Limited data on peanut response to picloram is available. Field trials were conducted near Tifton, GA from 2015-2017 to determine the effects of picloram plus 2,4-D (2,4-dichlorophenoxyacetic acid) on peanut growth and yield. Picloram plus 2,4-D was applied to ‘GA-06G' peanut at four different timings: preemergence (PRE), 30 d after planting (DAP), 60 DAP, and 90 DAP. At each timing, three rates of picloram plus 2,4-D were applied including the following: 1/10thX (0.18 + 0.67 kg ai/ha); 1/100thX (0.018 + 0.067 kg ai/ha); and 1/300thX (0.006 + 0.023 kg ai/ha). A non-treated control (NTC) or 0 rate was included for comparison. Peanut plant density was not influenced by any rate or timing of picloram plus 2,4-D. For peanut injury (leaf roll), a significant rate x timing interaction was observed (P=0.047). At 120 DAP, leaf roll was significant for the 1/10thX rate applied at 30, 60, and 90 DAP, the 1/100thX rate applied at 60 and 90 DAP, and for the 1/300thX rate applied at 90 DAP. When averaged over timing, peanut height at 120 DAP was significantly reduced by the 1/10thX and 1/100thX rates. When averaged over rate, peanut height reductions were greatest when picloram plus 2,4-D was applied at 60 DAP. When averaged over timing, only the 1/10thX rate caused significant yield reductions (11%). When averaged over rate, timing had no effect on yield (P=0.5403). Peanut fields unintentionally exposed to picloram plus 2,4-D rates ≤ 1/100thX can exhibit typical injury symptoms but most likely will not experience yield losses.
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Chamberlin, K. D., J. J. Baldessari, E. M. C. Mamani, and M. V. Moreno. "Screening of the Argentinean INTA peanut core collection with a molecular marker associated with resistance to Sclerotinia minor Jaggar." Peanut Science 47, no. 1 (2020): 9–16. http://dx.doi.org/10.3146/ps19-15.1.
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ABSTRACT Cultivated peanut, the third most important oilseed in the world, is consistently threatened by various diseases and pests. Sclerotinia minor Jagger (S. minor), the causal agent of Sclerotinia blight, is a major threat to peanut production in many countries and can reduce yield by up to 50% in severely infested fields. Host plant resistance will provide the most effective solution to managing Sclerotinia blight, but limited sources of resistance to the disease are available for use in breeding programs. Peanut germplasm collections are available for exploration and identification of new sources of resistance, but traditionally the process is lengthy, requiring years of field testing before those potential sources can be identified. Molecular markers associated with phenotypic traits can speed up the screening of germplasm accessions. The objective of this study was to genotype the peanut core collection of the Instituto Nacional de Tecnología Agropecuaria (INTA) Manfredi, Argentina, with a molecular marker associated with Sclerotinia blight resistance. One hundred and fifty-four (154) accessions from the collection were available and genotyped using the Simple Sequence Repeat (SSR) marker. Accessions from each botanical variety type represented in the core collection were identified as new potential sources of resistance and targeted for further evaluation in field tests for Sclerotinia blight resistance.
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Porter, W. M., J. Ward, R. K. Taylor, and C. B. Godsey. "A Note on the Application of an AgLeader® Cotton Yield Monitor for Measuring Peanut Yield: An Investigation in Two US states." Peanut Science 47, no. 2 (2020): 115–22. http://dx.doi.org/10.3146/ps19-16.1.
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ABSTRACT Previous researchers demonstrated the ability to adapt an AgLeader® Cotton Monitor to a peanut combine. It was demonstrated that the field weight could be accurately predicted with average errors of less than 10% across all trials when at least five calibration loads are applied. This project focused on expanding previous work performed at the University of Georgia and other peanut optical yield monitor work by incorporating a protective deflector plate for the sensors, obtaining multiple field weights, and using the peanut sale sheets to correlate yield monitor yield to sale weight. This study was a two-university, two-state effort, including Oklahoma State University (Oklahoma), and Mississippi State University (Mississippi). Data collected during this study included multiple loads which included yield monitor weight, field weight, field moisture content, and all the information presented on the standard USDA peanut grade sheet, when available. The multi-state effort allowed for the incorporation of the two major peanut types and for the incorporation of different soil types. The goal of this study was to develop guidelines for using, calibrating, and adapting the AgLeader® Cotton Monitor for peanut harvest. Five calibration loads referenced to buy-point net weight were typically needed to bring error within acceptable limits. Results indicated that multiple local calibrations were needed to ensure high data validity and yield estimation across multiple harvest environments. The data showed that peanut type (virginia, runner and spanish) and variable soil conditions impacted yield estimation.
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Bennett, R. S., and K. D. Chamberlin. "Resistance to Athelia rolfsii and Web Blotch in the U.S. Mini-core Collection." Peanut Science 47, no. 1 (2020): 17–24. http://dx.doi.org/10.3146/ps19-18.1.
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ABSTRACT Athelia rolfsii (=Sclerotium rolfsii) is a soilborne fungus that causes the disease commonly known as southern blight, southern stem rot, stem rot, and white mold. Despite the fact that A. rolfsii is one of the most destructive pathogens of peanut, the U.S. germplasm collection has not been evaluated for resistance to this pathogen. Therefore, 71 of the 112 accessions comprising the U.S. peanut mini-core collection were evaluated in the field for resistance to southern blight in 2016 to 2018 in Oklahoma. Moderate to low levels of southern blight were observed, but four accessions—CC125, CC208, CC559, and CC650—had low levels of disease in 2017 and 2018, the most favourable years for A. rolfsii. Ratings for web blotch, a yield-limiting foliar disease in some production areas caused by Didymella arachidicola, were also taken in 2017 and 2018, when outbreaks occurred. Five entries—CC287, CC155, CC149, CC812, and CC559—had between 10% and 20% disease in 2018, a year when over half of the mini-core accessions exhibited between 50% and 93% disease. Because cultivated peanut in the U.S. has a narrow genetic base, these results will be useful to breeders seeking additional sources of resistance to A. rolfsii and web blotch.
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Sidhu, S. S., E. van Santen, S. George, I. Small, and D. L. Wright. "Effects of Planting Date and Irrigation on Yield and Grade in Runner-type Peanut Cultivars in North Florida." Peanut Science 46, no. 2 (2019): 191–97. http://dx.doi.org/10.3146/ps19-2.1.
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ABSTRACT Peanuts (Arachis hypogaea L.) have been one of the most profitable crops in the southeastern coastal plains but with increasing cost of production, growers continually seek to lower inputs and enhance overall profitability of their farms. Peanut cultivars with high yield potential and disease resistance along with drought tolerance are therefore obvious choices for sustainable production. Runner-type peanut cultivars were evaluated for pod yield and grade for three yr. Five peanut cultivars were evaluated in 2014 and 2015 and six cultivars in 2016 at the North Florida Research and Education Center, University of Florida, Quincy, FL. Cultivar performance was observed at different planting dates, four in 2014 and three in 2015 and 2016, to evaluate impacts of early, mid, and late planting with and without irrigation. Georgia cultivar GA-12Y consistently yielded greater than the other varieties in all yr of the study. Average pod yield for GA-12Y was 5980 kg/ha for three yr compared to 5140 kg/ha, 4730 kg/ha, 4890 kg/ha for GA-06G, FloRun 107, and TUFRunner 511, respectively. Florida cultivar TUFRunner 297 yielded greater (5300 kg/ha) than the rest of Florida cultivars irrespective of the planting date and had higher proportion of total sound mature kernels (TSMK) compared to GA-12Y in two of the three yr. Planting date had no impact on peanut pod yield in 2014 and 2015. However, peanut yield for all the cultivars was higher at later planting dates in 2016. The advantage of irrigation was not always consistent in all the yr, likely due to high rainfall during the study yr, removing that advantage.
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Hurdle, Nicholas L., Timothy L. Grey, C. Pilon, W. Scott Monfort, and Eric P. Prostko. "Peanut Seed Germination and Radicle Development Response to Direct Exposure of Flumioxazin Across Multiple Temperatures." Peanut Science 47, no. 2 (2020): 89–93. http://dx.doi.org/10.3146/ps19-20.1.
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ABSTRACT Peanut injury in the field can occur from flumioxazin applied PRE, but this is associated with plants that have emerged, or are about to, emerge from soil. The direct effect of flumioxazin on peanut seed germination and radicle development has not been evaluated. Therefore, research was conducted to determine peanut seed radicle development response to flumioxazin at different concentrations (0.0, 0.01, 0.10, 1.0 and 10.0 ppb) when tested at multiple temperatures (20, 23, 26, and 29 C) in laboratory experiments on a thermogradient table. Data analysis indicated that flumioxazin concentration was not different from the nontreated control (0.0 ppb) for 0.01, 0.1, and 1.0 ppb for peanut germination. Flumioxazin at 10.0 ppb was different from all other treatments and the nontreated control. However, comparing linear regression models for each flumioxazin concentration across all temperatures indicated no differences for slope. These data indicate that when there is direct peanut seed exposure to flumioxazin at field application rates, there is no impact on germination and radicle development. Temperature was noted to affect radicle development greater than field application rates of flumioxazin. As temperature decreased, germination and radicle length was inhibited or decreased, respectively. Nomenclature: Flumioxazin, peanut, Arachis hypogaea (L.), radicle, seed germination
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Branch, W. D., and N. Brown. "Inheritance of an Albino-Virescent Leaf Mutant in the Cultivated Peanut (Arachis hypogaea L.)." Peanut Science 46, no. 2 (2019): 203–5. http://dx.doi.org/10.3146/ps19-3.1.
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ABSTRACT An Albino-Virescent Leaf mutant was recently found in an advanced Georgia peanut (Arachis hypogaea L.) breeding line, GA 082524. This breeding line was derived from the cross of ‘Georgia-02C' x (‘Georgia-01R' x ‘COAN'), none of which have exhibited any mutant phenotypes in the past. The Albino-Virescent leaf mutant was selected and reciprocal crosses made with GA 082524 to determine the inheritance of this unusual chlorophyll deficiency. F1 and F2 data indicated a single recessive gene, avl, controlled the Albino-Virescent leaf trait. Chi-square analysis indicated a good fit to the expected 3:1 segregation ratio. No maternal or cytoplasmic effects were detected among the progenies from reciprocal hybridization.
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Nayak, Jwalit J., Pranavkumar D. Gajjar, Sheikh M. Basha, and KSS Naik. "Interrelationship between stilbene producing ability and Aspergillus colonization on selected peanut (Arachis hypogaea L.) genotypes." Peanut Science 46, no. 2 (2019): 118–26. http://dx.doi.org/10.3146/ps19-4.1.
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ABSTRACT Stilbenes are phytoalexins expressed by plants to avoid/resist certain biotic and abiotic stresses. This study was envisioned to determine the interrelationship between stilbenes producing ability of peanut genotypes and Aspergillus colonization level. Stilbenes were induced in peanut cotyledon in vitro by soaking in water, cutting them into thin slices, and subsequently challenging them with Aspergillus flavus. Fungal colonization was then measured in the cotyledon slices. The results showed major differences in fungal colonization levels between the control (seed without stilbene induction) and stilbenes-induced seeds. This finding was further validated using twenty peanut genotypes to ensure the relationship between stilbenes producing ability of the seed and fungal colonization level. The result showed that of the 20 genotypes tested, seeds of genotypes K1504, K1620 and K1632 showed minimal fungal colonization compared to control seed (without stilbenes induction), while genotypes DRT40, Kadiri-7, Narayani, DRT43 and Tirupati-3 showed no fungal colonization. The differences in stilbenes content and composition of cotyledon slices was determined by HPLC to assess genetic differences in their stilbenes producing ability. Comparative evaluation of these data showed that the genotypes that showed no fungal colonization expressed significantly higher amounts of stilbenes compared to genotypes which expressed relatively lower amounts of stilbenes. Overall, these data suggest that the genotypes expressing high amounts of stilbenes were able to mitigate fungal colonization while the genotypes expressing relatively lower amounts of stilbenes sustained fungal colonization, which indicates that this technique may be useful for screening breeding population to identify genotypes capable of avoiding Aspergillus colonization and aflatoxin contamination.
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Haynes, J. M., N. Smith, A. K. Culbreath, K. R. Kirk, and D. J. Anco. "Effects of insecticides applied in-furrow with superabsorbent polymer on peanut cultivars infected with Tomato spotted wilt virus." Peanut Science 46, no. 2 (2019): 127–39. http://dx.doi.org/10.3146/ps19-7.1.
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ABSTRACT Spotted wilt of peanut (SWP) (Arachis hypogaea L.) caused by Tomato spotted wilt virus (TSWV; family Tospoviridae, genus Orthotospovirus) is a common disease that causes severe economic losses in peanut producing regions of the world. The causal agent is transmitted by thrips (Thysanoptera: Thripidae). Field experiments were conducted in 2017 and 2018 to determine if management of spotted wilt and subsequent productivity of peanut, including economic value, could benefit from applying a superabsorbent polymer (SAP) with standard in-furrow insecticides at planting. To determine this, two individual experiments were performed. In the first study, phorate and imidacloprid were individually applied with (2.24 kg/ha) or without SAP across cultivars susceptible (FloRun 157 or TUFRunner 511), moderately susceptible (Georgia 06G), and resistant (Sullivan or TifNV-High O/L) to TSWV. Nontreated controls were included in all experiments. The second study sought to determine the efficacy of different rates of SAP (0, 2.24, 5.6, and 8.97 kg/ha). The initial study was conducted in three locations across South Carolina and Georgia, while the second was conducted at Blackville, SC. In the first study, incidence of SWP was reduced (P = 0.0547) in multiple location-year analysis with a reduction of 9.4% observed in susceptible cultivars treated with phorate compared to untreated checks and those with imidacloprid. SAP did not affect final SWP incidence or economic value (P &gt; 0.05) and was not consistently significant for yield. From the SAP rate study, a linear relationship of decreasing SWP incidence was observed with increasing SAP application rates for both imidacloprid and phorate in 2017 and 2018. On a means comparison basis, SWP was lower than the no-SAP check at SAP rates of 5.56 and 8.97 kg/ha, but this did not necessarily translate into increased yield. Additional experiments are needed to elucidate the relationship superabsorbent polymer may have to susceptible cultivars and phorate.
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Virk, Gurpreet, Cristiane Pilon, and John L. Snider. "Impact of First True Leaf Photosynthetic Efficiency on Peanut Plant Growth under Different Early-Season Temperature Conditions." Peanut Science 46, no. 2 (2019): 162–73. http://dx.doi.org/10.3146/ps19-8.1.
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ABSTRACT Selecting planting dates with optimal temperatures for plant growth and development is important for successful crop production. Photosynthetic rates of peanut leaves under adverse environmental conditions have been widely studied; however, characterization of photosynthetic efficiency of first true leaves as well as its contribution to plant growth is not well elucidated. The objectives of this research were to assess the influence of first true leaves of peanut cultivars on plant growth under different temperature conditions during early growth and at the onset of flowering and to identify the photosynthetic components more closely linked with photosynthetic efficiency of the first true leaves. Experiments were conducted with April (early), May (optimum), and June (late) planting dates in 2017 and 2018. Cultivars Georgia-06G, Georgia-14N, and TifNV-High O/L were evaluated. Measurements were taken at three and five wks after planting, early season and the onset of flowering, respectively. Rapid development of first true leaves of peanut plants contributed to whole-plant growth in the early season and at the onset of flowering across the temperature conditions. Net photosynthesis of first true leaves was not impacted by temperature conditions in the early season or at the onset of flowering primarily due to greater activity of non-stomatal components associated with the thylakoid reactions. Whole-plant growth was more considerably associated with first true leaf area development than photosynthetic efficiency of those leaves in peanut plants.
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Hare, A. T., D. L. Jordan, R. G. Leon, et al. "Impact of Weed Management on Peanut Yield and Weed Populations the Following Year." Peanut Science 46, no. 2 (2019): 182–90. http://dx.doi.org/10.3146/ps19-9.1.
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ABSTRACT Field studies were conducted in 2016 and 2017 at two locations in North Carolina to evaluate common ragweed (Ambrosia artemiisifolia L.) (Lewiston-Woodville) and Palmer amaranth (Amanthus palmeri S. Wats) control (Rocky Mount), peanut (Arachis hypogaea L.) yield, and estimated economic return when herbicides were applied postemergence (POST) at 2 or 6 weeks after planting (WAP); 2 and 4 WAP; 4 and 6 WAP; and 2, 4, and 6 WAP. During the following growing season, cotton (Gossypium hirsutum L.) was planted directly into the same plots to determine the impact of weed management during the previous season on weed density. In absence of herbicides, peanut yield was 880 and 1110 kg/ha at Lewiston-Woodville and Rocky Mount, respectively. When weed control depended on a single herbicide application, yield ranged from 1760 to 2660 kg/ha at Lewiston-Woodville, and 2080 to 2480 kg/ha at Rocky Mount. When herbicides were applied twice, peanut yield ranged from 2690 to 3280 kg/ha at Lewiston-Woodville and 3420 to 3840 kg/ha at Rocky Mount. The greatest yields were recorded when herbicides were applied two or three times. Applying herbicides increased the estimated economic return of peanut compared to the non-treated control (NTC). In cotton the following year, common ragweed populations at Lewiston-Woodville were greater following the NTC or a single herbicide application 2 WAP compared to more intensive herbicide programs. Palmer amaranth density at Rocky Mount the following year in cotton was not affected by weed management the previous year in peanut. These results illustrate the relative importance of timing and duration of weed management for peanut and how they influence weed emergence in the following cotton rotational crop.
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Yang, Shubing, Ji Wang, Yongkang Cao, et al. "Clec7a Signaling in Microglia Promotes Synapse Loss Associated with Tauopathy." International Journal of Molecular Sciences 26, no. 7 (2025): 2888. https://doi.org/10.3390/ijms26072888.
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Alzheimer’s disease (AD) pathogenesis involves progressive synaptic degeneration, a process potentially driven by maladaptive microglial pruning activity. While synaptic loss is a hallmark of AD, the molecular signals triggering pathological microglia-mediated synaptic engulfment remain elusive. Clec7a—a key marker of disease-associated microglia (DAM)—is known to activate spleen tyrosine kinase (SYK) signaling, enhancing Aβ phagocytosis and neuroprotective functions in 5×FAD models. However, its role in regulating synapse–microglia interactions under tauopathic conditions remains undefined. Our analysis revealed a progressive activation of the Clec7a–SYK signaling axis in the hippocampus of PS19 tauopathy mice, correlating with disease progression. Spatial mapping demonstrated a significant co-localization of Clec7a with hippocampal microglia, suggesting cell-autonomous signaling. The pharmacological inhibition of Clec7a achieved multimodal therapeutic effects by attenuating microglial hyperreactivity, suppressing neuroinflammatory cytokine release, and restoring physiological synaptic turnover. Mechanistically, we identified MD2 as a synaptic “eat-me” signal on tauopathy-related synapses, recruiting Clec7a+ microglia to drive aberrant synaptic elimination in PS19 mice. Strikingly, Clec7a blockade rescued hippocampal-dependent memory deficits in behavioral tests. These findings position Clec7a as a context-dependent therapeutic target, with inhibition strategies showing particular promise for tauopathy-related synaptic degeneration.
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Li, Wen, Kent C. Sasse, Yulia Bayguinov, Sean M. Ward, and Brian A. Perrino. "Contractile Protein Expression and Phosphorylation and Contractility of Gastric Smooth Muscles from Obese Patients and Patients with Obesity and Diabetes." Journal of Diabetes Research 2018 (May 31, 2018): 1–14. http://dx.doi.org/10.1155/2018/8743874.
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Ingested food is received, mixed, and ground into chyme by distinct gastric motility patterns. Diabetes impairs gastric muscle function, but the mechanisms underlying diabetes-induced gastric muscle dysfunction are unknown. Here, we compared the expression and phosphorylation of Ca2+ sensitization and contractile proteins in human gastric muscles from obese nondiabetic and diabetic patients. We also compared the spontaneous phasic contractions and the contractile responses evoked by electrical field stimulation of cholinergic motor neurons. Fundus and antrum muscles were obtained from sleeve gastrectomies and were used in in vitro myobath contractile studies and for capillary electrophoresis and immunodetection of γ-actin, CPI-17, pT38-CPI-17, MYPT1, pT853-MYPT1, pT696-MYPT1, myosin light chain (MYL9), pS19-MYL9, myosin light chain kinase (MYLK), protein phosphatase-1δ (PP1δ), and Rho-associated kinase (ROCK2). In diabetic fundus muscles, MYLK, ROCK2, and PP1δ expression was unchanged; MYPT1 and CPI-17 expression was decreased; and the pT853/MYPT1 and pT38/CPI-17 ratios, but not the pT696/MYPT1 ratio, were increased. Although MYL9 expression was increased, the pS19/MYL9 ratio was unchanged in diabetic fundus muscles. In diabetic antrum muscles, MYLK and MYL9 expression was unchanged, but ROCK2, CPI-17, and PP1δ expression was decreased. The pT38/CPI-17 ratio was unchanged, while the pS19/MYL9, pT853/MYPT1, and pT696/MYPT1 ratios were decreased, consistent with the reduced ROCK2 expression. The frequencies of spontaneous phasic contractions from nondiabetic and diabetic gastric fundus and antrum muscles did not significantly differ from each other, regardless of age, sex, or diabetic status. The fold increases in the contractions of diabetic fundus and antrum muscles in response to increased frequencies of electrical field stimulation were significantly lower compared to nondiabetic fundus and antrum muscles. The altered contractile responses and the protein expression and phosphorylation in gastric muscles of obese patients with diabetes illustrate the importance of understanding how smooth muscle Ca2+ sensitization mechanisms contribute to gastric motility.
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Longo, Savannah, María Laura Messi, Zhong‐Min Wang, William Meeker, and Osvaldo Delbono. "Accelerated sarcopenia precedes learning and memory impairments in the P301S mouse model of tauopathies and Alzheimer's disease." Journal of Cachexia, Sarcopenia and Muscle, April 22, 2024. http://dx.doi.org/10.1002/jcsm.13482.
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AbstractBackgroundAlzheimer's disease (AD) impairs cognitive functions and peripheral systems, including skeletal muscles. The PS19 mouse, expressing the human tau P301S mutation, shows cognitive and muscular pathologies, reflecting the central and peripheral atrophy seen in AD.MethodsWe analysed skeletal muscle morphology and neuromuscular junction (NMJ) through immunohistochemistry and advanced image quantification. A factorial Analysis of Variance assessed muscle weight, NCAM expression, NMJ, myofibre type distribution, cross‐sectional areas, expression of single or multiple myosin heavy‐chain isoforms, and myofibre grouping in PS19 and wild type (WT) mice over their lifespan (1–12 months).ResultsSignificant weight differences in extensor digitorum longus (EDL) and soleus muscles between WT and PS19 mice were noted by 7–8 months. For EDL muscle in females, WT weighed 0.0113 ± 0.0005 compared with PS19's 0.0071 ± 0.0008 (P < 0.05), and in males, WT was 0.0137 ± 0.0001 versus PS19's 0.0069 ± 0.0006 (P < 0.005). Similarly, soleus muscle showed significant differences; females (WT: 0.0084 ± 0.0004; PS19: 0.0057 ± 0.0005, P < 0.005) and males (WT: 0.0088 ± 0.0003; PS19: 0.0047 ± 0.0004, P < 0.0001). Analysis of the NMJ in PS19 mice revealed a marked reduction in myofibre innervation at 5 months, with further decline by 10 months. NMJ pre‐terminals in PS19 mice became shorter and simpler by 5 months, showing a steep decline by 10 months. Genotype and age strongly influenced muscle NCAM immunoreactivity, denoting denervation as early as 5–6 months in EDL muscle Type II fibres, with earlier effects in soleus muscle Type I and II fibres at 3–4 months. Muscle denervation and subsequent myofibre atrophy were linked to a reduction in Type IIB fibres in the EDL muscle and Type IIA fibres in the soleus muscle, accompanied by an increase in hybrid fibres. The EDL muscle showed Type IIB fibre atrophy with WT females at 1505 ± 110 μm2 versus PS19's 1208 ± 94 μm2, and WT males at 1731 ± 185 μm2 versus PS19's 1227 ± 116 μm2. Similarly, the soleus muscle demonstrated Type IIA fibre atrophy from 5 to 6 months, with WT females at 1194 ± 52 μm2 versus PS19's 858 ± 62 μm2, and WT males at 1257 ± 43 μm2 versus PS19's 1030 ± 55 μm2. Atrophy also affected Type IIX, I + IIA, and IIA + IIX fibres in both muscles. The timeline for both myofibre and overall muscle atrophy in PS19 mice was consistent, indicating a simultaneous decline.ConclusionsProgressive and accelerated neurogenic sarcopenia may precede and potentially predict cognitive deficits observed in AD.
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Ejaz, Saima, Jack Sternburg, Hongmin Wang, Rezvani Khosrow, and Xuejun Wang. "Abstract We132: Genetic Blockade of PKA-mediated Phosphoregulation of 26S Proteasomes Exacerbates Pathology in Both the Brain and Heart of an Alzheimer’s Disease Model." Circulation Research 135, Suppl_1 (2024). http://dx.doi.org/10.1161/res.135.suppl_1.we132.
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Background: Alzheimer’s disease (AD) patients often display not only cognitive impairment but also cardiac malfunction, but the underlying factors remain elusive. Phosphorylation of Ser14 of RPN6 (p-S14-RPN6) is required for cAMP/protein kinase A (PKA) to activate 26S proteasomes. Proteasome priming is implicated in the protection by cAMP-PKA augmentation against AD, but this remains to be established. Hence, we conducted this study to address these critical gaps. Methods: The Rpn6 S14A knock-in mice recently created for genetic blockade of p-S14-Rpn6 were crossbred with the PS19 tauopathy model (Jackson Lab Stock # 008169). Littermate wild type (WT), PS19, and PS19::S14A mice were compared. Cardiac function was evaluated with echocardiography (Echo). Hippocampal and myocardial tissues were used for western blot analyses (WB) and histopathology. Results: Increases in hippocampal insoluble tau proteins and in total and K48-linked ubiquitin conjugates were markedly greater in PS19::S14A mice than PS19 and WT mice. WBs for PSD95, synaptotagmin, Neu N, GFAP, and IBA1 revealed exacerbated synaptic loss, neuronal loss, gliosis, and microglial activation in the hippocampus of PS19::S14A mice in comparison to PS19 and WT mice. A more significant decline in cognitive function indicated by object recognition index was found in PS19::S14A mice vs. PS19 mice at 6 months. More interestingly, as compared to PS19 and WT littermates, PS19::S14A mice showed greater increases in myocardial tau proteins, ubiquitin conjugates, and cleaved caspase 3 and displayed more cardiac fibrosis, as reflected by increased mRNA expression of collagen 1 and picrosirius red staining. Echo revealed that PS19::S14A had significantly reduced fractional shortening, ejection fraction, stroke volume, and cardiac output at 9 months. Conclusions: The findings of this study demonstrate that genetic blockade of p-S14-RPN6 exacerbates tauopathy pathology in both the brain and heart. This is the first to have established the role of p-S14-RPN6 and, by extension, the significance of PKA-mediated proteasome activation in AD/tauopathy. Proteasome activation via augmentation of cAMP/PKA signaling should be explored for the alleviation of AD-associated brain and cardiac pathologies.
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Soni, Disha M., Peter Bor‐Chian Lin, Audrey Lee‐Gosselin, et al. "Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy." Alzheimer's & Dementia, June 26, 2024. http://dx.doi.org/10.1002/alz.14078.
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AbstractINTRODUCTIONA noncoding variant (rs35349669) within INPP5D, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well‐studied in amyloid pathology, its role in tau pathology remains unclear.METHODSPS19 Tauopathy mice were crossed with Inpp5d‐haplodeficient (Inpp5d+/−) mice to examine the impact of Inpp5d in tau pathology.RESULTSIncreased INPP5D expression correlated positively with phospho‐Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up‐regulation of genes associated with immune response and cell migration.DISCUSSIONOur findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient‐Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits.Highlights The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model. INPP5D expression is associated with tau pathology. Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho‐Tau levels. Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration. These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.
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Schweighauser, Manuel, Alexey G. Murzin, Jennifer Macdonald, et al. "Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau." Acta Neuropathologica Communications 11, no. 1 (2023). http://dx.doi.org/10.1186/s40478-023-01658-y.
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AbstractMice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice.
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Pankiewicz, Joanna E., Anita M. Lizińczyk, Leor A. Franco, Jenny R. Diaz, Alexandra Gootman, and Martin J. Sadowski. "Role of Peroxiredoxin 6 in the Development of Tau Pathology." Alzheimer's & Dementia 19, S13 (2023). http://dx.doi.org/10.1002/alz.072575.
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AbstractBackgroundIn Alzheimer’s disease (AD) and fronto‐temporal dementia excess of hyperphosphorylated tau (p‐tau) assembles into neurofibrillary tangles (NFTs). NFT‐bearing neurons are associated with A1 neurotoxic astrocytes and neurodegenerative phenotype microglia (MGnD). A1 astrocytes lose their neuron‐supporting properties and along with MGnD contribute importantly to the degeneration of NFT‐bearing neurons. MGnD and A1 astrocytes also reciprocally stimulate their pathological phenotypes. Factors endowing astrocytes with resistance to A1 transformation remain unknown. Astrocytes express peroxiredoxin 6 (PRDX6) protein, which glutathione peroxidase and phospholipase 2 enzymatic activities enable repair of oxidatively damaged cell membranes and cell‐to‐cell signaling. PRDX6 upregulation has been noted in astrocytes associated with NFT‐bearing neurons in AD, yet its precise role in the development of tau pathology remains unknown. To this end we created new MAPTP301S transgenic mouse lines featuring Prdx6 haplodeficiency and hemizygous knock‐in of the overexpressing Prdx6 transgene.MethodMAPTP301S (PS19/Prdx6+/+) mice were crossed with Prdx6−/− mice and with Prdx6129X1/SvJ allele knock‐in mice, which feature wild‐type PRDX6 overexpression. Resulting lines PS19/Prdx6+/−, PS19/Prdx6+/+, and PS19/Prdx6Tg showed 0.4:1:2 ratio of brain Prdx6 mRNA level, while hTau and Gfap mRNA levels were similar. All lines were neuropathologically characterized at the age of 9.5 months.ResultBrain atrophy determined by quantifying hippocampal and lateral ventricular volumes and the hippocampal p‐tau load show inverse relations with the Prdx6 gene dose. The load of GFAP+ astrocytes and the C3+/GFAP+ ratio used as a surrogate A1 phenotype marker also vary inversely with the Prdx6 expression. The load of IBA1+ microglia show inverse relation with the Prdx6 gene dose, while the CD68+/IBA1+ index used as a surrogate marker of microglia phagocytic activity show direct correlation.ConclusionAttenuation of the pathological phenotype in PS19/Prdx6Tg line and its worsening in PS19/Prdx6+/− line evidence a neuroprotective role of PRDX6 in tau‐mediated neurodegeneration. Observed inverse relation between the Prdx6 gene dose and astrocytic C3 expression and microglia activation suggests PRDX6 endows astrocytes with resistance to A1 transition, which in turn hampers microglia activation. Analysis of astrocyte and microglia transcript from PS19/Prdx6+/−, PS19/Prdx6+/+, and PS19/Prdx6Tg lines focused on A1 and MGnD activation markers is underway.
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Brody, A. Harrison, Sarah Helena Nies, Fulin Guan, et al. "Alzheimer risk gene product Pyk2 suppresses tau phosphorylation and phenotypic effects of tauopathy." Molecular Neurodegeneration 17, no. 1 (2022). http://dx.doi.org/10.1186/s13024-022-00526-y.
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Abstract Background Genetic variation at the PTK2B locus encoding the protein Pyk2 influences Alzheimer’s disease risk. Neurons express Pyk2 and the protein is required for Amyloid-β (Aβ) peptide driven deficits of synaptic function and memory in mouse models, but Pyk2 deletion has minimal effect on neuro-inflammation. Previous in vitro data suggested that Pyk2 activity might enhance GSK3β-dependent Tau phosphorylation and be required for tauopathy. Here, we examine the influence of Pyk2 on Tau phosphorylation and associated pathology. Methods The effect of Pyk2 on Tau phosphorylation was examined in cultured Hek cells through protein over-expression and in iPSC-derived human neurons through pharmacological Pyk2 inhibition. PS19 mice overexpressing the P301S mutant of human Tau were employed as an in vivo model of tauopathy. Phenotypes of PS19 mice with a targeted deletion of Pyk2 expression were compared with PS19 mice with intact Pyk2 expression. Phenotypes examined included Tau phosphorylation, Tau accumulation, synapse loss, gliosis, proteomic profiling and behavior. Results Over-expression experiments from Hek293T cells indicated that Pyk2 contributed to Tau phosphorylation, while iPSC-derived human neuronal cultures with endogenous protein levels supported the opposite conclusion. In vivo, multiple phenotypes of PS19 were exacerbated by Pyk2 deletion. In Pyk2-null PS19 mice, Tau phosphorylation and accumulation increased, mouse survival decreased, spatial memory was impaired and hippocampal C1q deposition increased relative to PS19 littermate controls. Proteomic profiles of Pyk2-null mouse brain revealed that several protein kinases known to interact with Tau are regulated by Pyk2. Endogenous Pyk2 suppresses LKB1 and p38 MAPK activity, validating one potential pathway contributing to increased Tau pathology. Conclusions The absence of Pyk2 results in greater mutant Tau-dependent phenotypes in PS19 mice, in part via increased LKB1 and MAPK activity. These data suggest that in AD, while Pyk2 activity mediates Aβ-driven deficits, Pyk2 suppresses Tau-related phenotypes.
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Frasineanu, Anca Gabriela, Stephanie L. Gupton, and Stephanie Gupton. "Studying the Role of Brain Enriched E3 Ubiquitin Ligase TRIM9 in Alzheimer’s Disease." Alzheimer's & Dementia 20, S1 (2024). https://doi.org/10.1002/alz.085299.
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AbstractBackgroundIn the last decade, we have demonstrated that the brain‐enriched E3 ubiquitin ligase TRIM9 regulates cytoskeletal dynamics, membrane remodeling, and netrin‐dependent signaling pathways in all stages of neuron development, including the maturation of dendritic spines and electrophysiological activity. Moreover, TRIM9 protein levels increase in the adult brain and are maintained throughout adulthood. In the adult mouse TRIM9 is enriched within the postsynaptic density (PSD), a proteinaceous rich region in the post synapse, containing neurotransmitter receptors, scaffolding proteins, and cytoskeletal elements. The PSD proteome is significantly altered in adolescent mice when TRIM9 is lost, which is linked to changes in synaptic function. Our published proximity labelling experiments to characterize the TRIM9 interactome identified several proteins implicated in synaptic function and Alzheimer’s disease (AD), including Tau.MethodCross‐referencing this list with a published dataset of differentially expressed proteins (123) in the hippocampal PSD of 9 month old Tau P301S mice (PS19 AD model) versus non‐transgenic control, revealed a significant percent (56 proteins, 45.5%) overlap. Here we investigate the role of TRIM9 in tau‐mediated neurodegeneration, since TRIM9 is poised to interact with many AD‐associated proteins, and published work indicates that TRIM9 expression in HEK293T cells increased aggregated tau species. Four genotypes were compared (Trim9+/+, Trim9‐/‐, Trim9+/+:PS19, and Trim9‐/‐:PS19), and 3‐4 animals per genotype and sex were used in each experiment. We analyzed changes in dendritic spine density of six month old murine cortical and hippocampal neurons using the Golgi‐Cox staining method. We also investigated changes in pathological tau accumulation, microglia and astrocytes activation using multiplexed immunofluorescence imaging and biochemical analysis.ResultIba1 positive microglia were significantly enriched in the hippocampus and entorhinal cortex of six month old Trim9‐/‐:PS19 mice compared to the other genotypes. Pathological tau accumulation had an increase trend in the hippocampus of Trim9‐/‐:PS19 mice compared to PS19 only mice.ConclusionDeletion of Trim9 exacerbated the progression of Alzheimer’s disease in six month old PS19 mice. Future experiments will use primary cultured hippocampal neurons to further determine the mechanism through which Trim9 deletion increases pathological tau accumulation.
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Zubia, Mario V., Adeline J. H. Yong, Kristen M. Holtz, Eric J. Huang, Yuh Nung Jan, and Lily Y. Jan. "TMEM16F exacerbates tau pathology and mediates phosphatidylserine exposure in phospho-tau-burdened neurons." Proceedings of the National Academy of Sciences 121, no. 27 (2024). http://dx.doi.org/10.1073/pnas.2311831121.
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TMEM16F is a calcium-activated phospholipid scramblase and nonselective ion channel, which allows the movement of lipids bidirectionally across the plasma membrane. While the functions of TMEM16F have been extensively characterized in multiple cell types, the role of TMEM16F in the central nervous system remains largely unknown. Here, we sought to study how TMEM16F in the brain may be involved in neurodegeneration. Using a mouse model that expresses the pathological P301S human tau (PS19 mouse), we found reduced tauopathy and microgliosis in 6- to 7-mo-old PS19 mice lacking TMEM16F. Furthermore, this reduction of pathology can be recapitulated in the PS19 mice with TMEM16F removed from neurons, while removal of TMEM16F from microglia of PS19 mice did not significantly impact tauopathy at this time point. Moreover, TMEM16F mediated aberrant phosphatidylserine exposure in neurons with phospho-tau burden. These studies raise the prospect of targeting TMEM16F in neurons as a potential treatment of neurodegeneration.
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Choi, Yun-Beom, Ambrose A. Dunn-Meynell, Michelle Marchese, et al. "Erythropoietin-derived peptide treatment reduced neurological deficit and neuropathological changes in a mouse model of tauopathy." Alzheimer's Research & Therapy 13, no. 1 (2021). http://dx.doi.org/10.1186/s13195-020-00766-4.
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Abstract Background Prominent activation of microglial immune/inflammatory processes is a characteristic feature of brains of patients with tauopathies including Alzheimer’s disease (AD), suggesting that neuroinflammation may be a critical factor in their pathogenesis. Strategies aimed at developing new therapeutics for tauopathies based on anti-inflammation or immunomodulation are likely to be promising avenues of research. We previously developed JM4—a 19’mer cyclic peptide derived from the first loop of human erythropoietin. This peptide possesses beneficial immune modulatory and tissue protective effects while lacking the undesirable side effects of full-length erythropoietin. In this preclinical study, we investigated the effect of chronic JM4 treatment on the PS19 mouse that carries the P301S mutant human tau gene, linked to a form of frontotemporal dementia. This transgenic mouse has been widely used as a model of tauopathies including AD and related dementias. Methods Daily subcutaneous treatment of female PS19 mice with JM4 was initiated before disease onset and continued on for the animals’ lifespan. The progression of neurological deficit and the lifespan of these mice were assessed. To evaluate the effect of JM4 treatment on cognition of these animals, the PS19 mice underwent Barnes maze test and elevated plus maze test. In addition, neuronal loss, phosphorylated tau aggregation, and microglial activation were assessed using immunohistochemistry of PS19 mouse brain sections. Results JM4 treatment of PS19 mice initiated before disease onset reduced neurological deficit, prolonged lifespan, and rescued memory impairment. The beneficial effects of JM4 were accompanied by reductions in neuronal loss, phosphorylated tau aggregation, and microglial activation in the PS19 mouse brain. Limitations Use of a single dose of JM4 and female mice only. Conclusion JM4 is a potential novel therapeutic agent for the treatment of tauopathies including AD and related dementias.
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Thangavel, Mohankumar, Chengju Tian, Isabel Reyes, and Arjun V. Masurkar. "Presynaptic mechanisms of impaired long term potentiation of lateral entorhinal cortex input to CA1 in the PS19 mouse model of tauopathy." Alzheimer's & Dementia 20, S1 (2024). https://doi.org/10.1002/alz.086703.
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AbstractBackgroundHow tauopathy disrupts direct entorhinal cortex (EC) inputs to CA1 and their plasticity is understudied, despite its critical role in memory. Moreover, dysfunction of lateral EC (LEC) input is less clear, despite its relevance to early Alzheimer’s disease pathogenesis. Here we examined how tau impacts long‐term potentiation (LTP) of LEC→CA1 input in a transgenic model of tauopathy.MethodAcute hippocampal slices were prepared from PS19 and WT mice (8‐10 mo. old, M/F) in which LEC had been injected with an AAV expressing channelrhodopsin ChR2. Ex vivo recordings were achieved with blue LED light to excite LEC axons and an extracellular field electrode in stratum lacunosum moleculare (SLM) of distal CA1 to record field responses. Input‐output curves were established using 25‐100% LED power for field postsynaptic excitatory potentials (fEPSPs) with inhibition blocked (GABAA: 2mm SR95531, GABAB: 1mm CGP55845). LTP of fEPSPs was elicited after a 10” baseline using an LED theta burst stimulation (TBS). Paired pulse ratio (PPR) of fEPSPs was elicited with LED stimulation of 2 pulses at 20Hz. Fluorescence immunohistochemistry (IHC) was performed in separate mice using antibodies to N‐type calcium channels.ResultAll results are based on n = 4‐8/sex/genotype. The LEC fEPSP was of reduced magnitude in female PS19 versus WT mice, while unchanged across genotype in male mice. TBS induced a late‐onset LTP (147% at 45”) of the LEC fEPSP in female WT mice, which was significantly reduced in female PS19 mice (p = 0.0051). There was no LTP reduction in male mice. LTP in female WT mice was associated with a PPR reduction that was reversed by the addition of the N‐type calcium channel blocker w‐conotoxin GVIA, all of which did not occur in PS19 mice (p<0.0001). PPR was appropriately reduced in male mice across genotype. IHC of N‐type calcium channels showed reduced fluorescence in the SLM of female PS19 mice versus WT.ConclusionIn PS19 mice, the impact of tau on LEC→CA1 input is sex‐dependent, with reduced LEC‐driven excitation and LTP only in female mice. A reduction in presynaptic N‐type calcium channels in PS19 mice may serve as a presynaptic mechanism for the reduced plasticity.
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Williams, Tristan, Alejandra Jolie Ruiz, Angelica Maria Ruiz, et al. "Impact of APOE genotype on prion-type propagation of tauopathy." Acta Neuropathologica Communications 10, no. 1 (2022). http://dx.doi.org/10.1186/s40478-022-01359-y.
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AbstractApolipoprotein (APOE) is a major risk factor of Alzheimer’s disease (AD), with the E2, E3 and E4 isoforms differentially regulating the burden of AD-associated neuropathologies, such as amyloid β and tau. In AD, pathological tau is thought to spread along neuroanatomic connections following a prion-like mechanism. To provide insights into whether APOE isoforms differentially regulate the prion properties of tau and determine trans-synaptic transmission of tauopathy, we have generated human P301S mutant tau transgenic mice (PS19) that carry human APOE (APOE2, APOE3 or APOE4) or mouse Apoe allele. Mice received intrahippocamal injections of preformed aggregates of K18-tau at young ages, which were analyzed 5 months post-inoculation. Compared to the parental PS19 mice with mouse Apoe alleles, PS19 mice expressing human APOE alleles generally responded to K18-tau seeding with more intense AT8 immunoreactive phosphorylated tau athology. APOE3 homozygous mice accumulated higher levels of AT8-reactive ptau and microgliosis relative to APOE2 or APOE4 homozygotes (E3 > E4~2). PS19 mice that were heterozygous for APOE3 showed similar results, albeit to a lesser degree. In the timeframe of our investigation, we did not observe significant induction of argentophilic or MC1-reactive neurofibrillary tau tangle in PS19 mice homozygous for human APOE. To our knowledge, this is the first comprehensive study in rodent models that provides neuropathological insights into the dose-dependent effect of APOE isoforms on phosphorylated tau pathology induced by recombinant tau prions.