Academic literature on the topic 'Amyloidogenic pathway'

The BRICHOS domain decreases aggregation of designed amyloidogenic proteins expressed in the secretory pathway and reduces their negative effect on the proteasomal system. BRICHOS binds to aggregated forms of the amyloidogenic proteins and thereby prevents further aggregation and increases solubility.

An increasing amount of evidence supports the notion that cytotoxic effects of amyloid-βpeptide (Aβ), the main constituent of senile plaques in Alzheimer's disease (AD), are strongly associated with its ability to interact with membranes of neurons and other cerebral cells. Aβis derived from amyloidogenic cleavage of amyloid precursor protein (AβPP) byβ- andγ-secretase. In the nonamyloidogenic pathway, AβPP is cleaved byα-secretases. These two pathways compete with each other, and enhancing the non-amyloidogenic pathway has been suggested as a potential pharmacological approach for the treatment of AD. Since AβPP,α-,β-, andγ-secretases are membrane-associated proteins, AβPP processing and Aβproduction can be affected by the membrane composition and properties. There is evidence that membrane composition and properties, in turn, play a critical role in Aβcytotoxicity associated with its conformational changes and aggregation into oligomers and fibrils. Understanding the mechanisms leading to changes in a membrane's biophysical properties and how they affect AβPP processing and Aβtoxicity should prove to provide new therapeutic strategies for prevention and treatment of AD.

In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the β- and γ-secretases to release the Aβ (amyloid-β) peptide that is neurotoxic and aggregates in the brains of patients suffering from Alzheimer's disease. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain, precluding deposition of intact Aβ peptide. The cellular form of the PrPC (prion protein) undergoes reactive oxygen species-mediated β-cleavage within the copper-binding octapeptide repeats or, alternatively, α-cleavage within the central hydrophobic neurotoxic domain. In addition, PrPC is shed from the membrane by the action of a zinc metalloprotease. Members of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteases, notably ADAM10 and TACE (ADAM17) display α-secretase activity towards APP and appear to be responsible for the α-cleavage of PrPC. The amyloidogenic cleavage of APP by the β- and γ-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrPC into the infectious form PrPSc also appears to occur in these membrane domains.

One of the pathogenic systems of Alzheimer’s disease (AD) is the formation ofβ-amyloid plaques in the brains of patients, and amyloidogenic activity becomes one of the therapeutic targets. Here, we report wogonin, one of the major active constituting components inScutellaria baicalensis, which has the neuroprotective effects on amyloid-βpeptides- (Aβ-) induced toxicity. Oral wogonin treatment improved the performance of triple transgenic AD mice (h-APPswe, h-Tau P301L, and h-PS1 M146V) on the Morris water maze, Y-maze, and novel object recognition. Furthermore, wogonin activated the neurite outgrowth of AD cells by increasing neurite length and complexity of Tet-On Aβ42-GFP SH-SY5Y neuroblastoma cells (AD cells) and attenuated amyloidogenic pathway by decreasing the levels ofβ-secretase, APPβ-C-terminal fragment, Aβ-aggregation, and phosphorylated Tau. Wogonin also increased mitochondrial membrane potential (∆ψm) and protected against apoptosis by reducing the expression of Bax and cleaved PARP. Collectively, these results conclude that wogonin may be a promising multifunctional drug candidate for AD.

Abstract Light chain (LC) amyloidosis (AL) involves the toxic aggregation of amyloidogenic immunoglobulin LCs secreted from a clonal expansion of diseased plasma cells. Current AL treatments use chemotherapeutics to ablate the AL plasma cell population. However, no treatments are available that directly reduce the toxic LC aggregation involved in AL pathogenesis. An attractive strategy to reduce toxic LC aggregation in AL involves enhancing endoplasmic reticulum (ER) proteostasis in plasma cells to reduce the secretion and subsequent aggregation of amyloidogenic LCs. Here, we show that the ER proteostasis regulator compound 147 reduces secretion of an amyloidogenic LC as aggregation-prone monomers and dimers in AL patient–derived plasma cells. Compound 147 was established to promote ER proteostasis remodeling by activating the ATF6 unfolded protein response signaling pathway through a mechanism involving covalent modification of ER protein disulfide isomerases (PDIs). However, we show that 147-dependent reductions in amyloidogenic LCs are independent of ATF6 activation. Instead, 147 reduces amyloidogenic LC secretion through the selective, on-target covalent modification of ER proteostasis factors, including PDIs, revealing an alternative mechanism by which this compound can influence ER proteostasis of amyloidogenic proteins. Importantly, compound 147 does not interfere with AL plasma cell toxicity induced by bortezomib, a standard chemotherapeutic used to ablate the underlying diseased plasma cells in AL. This shows that pharmacologic targeting of ER proteostasis through selective covalent modification of ER proteostasis factors is a strategy that can be used in combination with chemotherapeutics to reduce the LC toxicity associated with AL pathogenesis.

Mucopolysaccharidosis type I (MPS I) is caused by genetic deficiency of α-l-iduronidase and impairment of lysosomal catabolism of heparan sulfate and dermatan sulfate. In the brain, these substrates accumulate in the lysosomes of neurons and glial cells, leading to neuroinflammation and neurodegeneration. Their storage also affects lysosomal homeostasis-inducing activity of several lysosomal proteases including cathepsin B (CATB). In the central nervous system, increased CATB activity has been associated with the deposition of amyloid plaques due to an alternative pro-amyloidogenic processing of the amyloid precursor protein (APP), suggesting a potential role of this enzyme in the neuropathology of MPS I. In this study, we report elevated levels of protein expression and activity of CATB in cortex tissues of 6-month-old MPS I (Idua -/- mice. Besides, increased CATB leakage from lysosomes to the cytoplasm of Idua -/- cortical pyramidal neurons was indicative of damaged lysosomal membranes. The increased CATB activity coincided with an elevated level of the 16-kDa C-terminal APP fragment, which together with unchanged levels of β-secretase 1 was suggestive for the role of this enzyme in the amyloidogenic APP processing. Neuronal accumulation of Thioflavin-S-positive misfolded protein aggregates and drastically increased levels of neuroinflammatory glial fibrillary acidic protein (GFAP)-positive astrocytes and CD11b-positive activated microglia were observed in Idua -/- cortex by confocal fluorescent microscopy. Together, our results point to the existence of a novel CATB-associated alternative amyloidogenic pathway in MPS I brain induced by lysosomal storage and potentially leading to neurodegeneration.

As a promising prevention and therapeutic intervention in Alzheimer’s disease, natural food dyes curcumin could obviously inhibit the generation of Aβ, but the mechanism is not fully defined. This study aims to investigate the effects of curcumin on the amyloidogenic pathway of APP in vitro. Plasmids APPswe and BACE1-mychis were transiently co-transfected into SH-SY5Y and HEK293 cells. Then, they were treated with curcumin at 0, 1.25, 5, 20 μmol/L for 24 h, or with curcumin at 5μmol/L for 0, 12, 24 and 48 h for the time course assay. Our findings showed that curcumin could inhibit the expression of the APP at mRNA level; the expression of the BACE1 and C99 at mRNA and protein levels, furthermore it could inhibit the generation of Aβ40/42, and those changes were dose-time dependent (p<0.05). Our study indicates that Aβ40/42 generation inhibition effect of curcumin might due to its influence on amyloidogenic pathway. This may provide important experimental basis for AD treatment with curcumin.

La protéine précurseur du peptide amyloïde (APP) est un élément central dans l'apparition et le développement de la maladie d'Alzheimer. L'APP possède deux voies de maturations distinctes. La maturation dite amyloïdogénique, via la béta-sécrétase, a principalement lieu au niveau des endosomes et entraine la production de peptides béta-amyloïdes neurotoxiques au-delà d'un certain seuil. La voie non-amyloïdogénique, via l'alpha-sécrétase, a quant à elle lieu au niveau de la membrane plasmique et entraîne la libération de fragments solubles sAPP alpha; neuroprotecteurs. Dans un premier temps, nos travaux ont mis en évidence que le récepteur de la sérotonine de type 4 (5-HT4R), l'alpha-sécrétase ADAM10 et l'APP forment un complexe protéique et que le récepteur 5-HT4 est capable de moduler à la fois l'adressage membranaire de l'alpha-sécrétase ADAM10 et de l'APP mais aussi leur maturation. Par cette modulation, le récepteur 5-HT4 peut favoriser de façon constitutive la libération de sAPP alpha. Dans un second temps, nous avons mis en place une approche protéomique, basée sur la recherche de protéines interagissant avec ce complexe et pouvant influencer le trafic cellulaire de l'ADAM10 ou de l'APP et favoriser la voie non-amyloïdogénique. Ces travaux nous permettent d'émettre des hypothèses originales quant aux mécanismes communs de régulation, à la fois de l'endocytose et du trafic du récepteur 5-HT4, de l'ADAM10 et de l'APP. Ces mécanismes mettent en cause le complexe AP-2 et un autre complexe protéique impliqué dans le trafic intracellulaire du précurseur de la protéine amyloïde<br>The amyloid precursor protein (APP) is the key element in the appearance and the development of Alzheimer's disease (AD). Basically, APP can be processed following two maturation pathways. The fist one, named the amyloidogenic pathway, involves a secretase, occurs mostly in the endosomes and leads to the release ofbeta-amyloïd peptides that are neurotoxics if overproduced. The second one, named the non-amyloidogenic pathway, involves analpha-secretase, occurs mostly at the plasma membrane and leads to the release of soluble APP alpha fragments that are neuroprotective. First, our work demonstrated that a serotonin receptor, the 5-HT4 receptor (5-HT4R), is able to form a protein complex with the alpha-secretase ADAM10 and APP and that this receptor could modulate ADAM10 and APP trafficking and maturation. By this way, the 5-HT4 receptor is able to increase ADAM10 and APP cell surface localization and to constitutively promote sAPP alpha release. In a second time, using an unbiased proteomic approach, we focused on the quest of protein partners able to interact with this complex and to promote the non-amyloïdogenic pathway. This work allowed us to propose original hypothesis about shared mechanisms able to regulate 5-HT4R, APP and ADAM10 endocytosis and trafficking. These mechanisms involve the AP-2 complex and another protein complex involved in the cellular trafficking of the amyloid precursor protein

Un ensemble des données cohérentes de la littérature plaide en faveur d'une relation entre une baisse d'activité de la voie de signalisation de la vitamine A, des altérations de la plasticité synaptique et des déficits mnésiques spécifiques associés au vieillissement. Une diminution de l'activité de cette voie de signalisation est également évoquée dans les processus neurodégénératifs caractéristiques de la maladie d'Alzheimer. Dans ce contexte, les objectifs de ce travail étaient de mieux comprendre les conséquences neuro-anatomiques et fonctionnelles d'une baisse d'activité de la voie de signalisation de la vitamine A. Notre approche expérimentale a mis en œuvre 2 modèles animaux, un modèle de carence vitaminique A qui induit spécifiquement une baisse d'activité de sa voie de signalisation et un modèle d'hypothyroïdie dont il a été montré qu'il induit aussi une hypoactivité de la voie de signalisation de la vitamine A. La démarche expérimentale conduite chez les rats carencés en vitamine A comporte deux volets : (i) un volet mettant en œuvre l’imagerie et la spectroscopie RMN, (ii) un volet moléculaire consacrée à l’étude de l’expression de gènes cibles des rétinoïdes impliqués dans le processus amyloïdogène. Les mesures ont été réalisées, d'une part, chez des animaux soumis à un régime dépourvu en vitamine A pendant 10 semaines et d'autre part, chez des animaux soumis à ce même régime pendant une durée de 13 ou 14 semaines. Une partie des animaux carencés a été traitée par de l'AR. Les résultats montrent que dès 10 semaines de carence, les animaux présentent une altération du métabolisme et de son action cellulaire de la vitamine A qui se traduit par (i) une diminution significative du taux de vitamine A sérique, (ii) une diminution du taux d'ARNm codant pour les récepteurs RAR, dans le cerveau entier, le striatum, l'hippocampe et de manière moins prononcée le cortex des animaux. Après 10 semaines de régime dépourvu en vitamine A, des modifications métaboliques ont été mises en évidence essentiellement dans le cortex. Elles se traduisent par une hausse du (i) NAA/Cr, marqueur de la densité neuronale corrigée par une administration d'AR, et (ii) du GSH/Cr, indicateur du potentiel antioxydant cellulaire dans cette structure. Au plan anatomique, un ralentissement de la croissance cérébrale a été observé dés la 7ème semaine de régime. Une diminution du volume hippocampique et une augmentation des espaces ventriculaires ont été observées à partir de 11 semaines de carence. Au plan moléculaire, aucune modification de l'expression du gène codant pour APP, ou du rapport APP770-751/APP695, considéré comme un indicateur précoce de la MA n'a été observée après 10 semaines de carence. Après 14 semaines de régime dépourvu en vitamine A, de profondes modifications métaboliques sont observées dans les trois structures à savoir le cortex, l’hippocampe et le striatum. Au plan moléculaire, les principaux résultats suggèrent un basculement du processus biochimique de dégradation de la protéine APP en faveur de la voie amyloïdogénique dans le cortex, et par voie de conséquence en faveur de la formation du peptide Aß. Cependant, aucune modification du taux protéique des peptides Aß n'a été mise en évidence dans le cortex et l'hippocampe des rats carencés. Le modèle d'hypothyroïdie que nous avons mis en oeuvre entraine bien une hypoactivité de la voie de signalisation de la T3, observée dans l'hippocampe des animaux et une diminution du taux d'ARNm codant pour RARß observée dans le cortex des rats hypothyroïdiens. Au plan moléculaire, l'augmentation du rapport APP770-751/APP695 a été observée chez les rats rendus hypothyroïdiens par rapport aux rats témoins. Comme chez les rats carencés en vitamine A, les indicateurs de la voie physiologique ne sont que très faiblement affectés chez les rats rendus hypothyroïdiens<br>Some data reveal that retinoid hyposignalling, presumably resulting from decreased bioavailability of retinoid ligands naturally, was shown to result in aging-related synaptic plasticity and long term potentiation (LTP) alterations as well as in aging-related decline of cognitive function. Moreover, genetic, metabolic and dietary evidence has been provided for a defective retinoid metabolism in Alzheimer disease (AD). Thus, key steps of the amyloid production process are under the control of proteins whose expression is positively regulated by RA in vitro. In this context, the aims of this work were to better understand neuro-anatomical and functionnal consequences of retinoid signaling brain hypoactivity. Our experimental method uses two animal models: a Vitamin A deficiency model which induce especially an hypoactivity of retinoid pathway, and an hypothyroid model which was also characterized by an hypoactivity of retinoid pathway. In the fisrt model, two main approch were used : (i) an NMR imaging and spectroscopy approach, (ii) a molecular approach to study expression of retinoid target genes implicated in amyloidogenic process. NMR results showed that VAD induces severe anatomic and metabolic disorders in particular a slowing of brain growth, hippocampus atrophy, and a decrease of NAA/Cr, marker of neuronal density which was observed in cortex, hippocampus and striatum. Molecular results reveal a vitamin A deficiency-related dysregulation of the amyloid pathway in the cortex of rats, which is known to be the first brain area altered by AD development. In this area, 14 weeks of deprived diet induces physiological dysregulation in the modulation of RA target genes leading to an increased amount of ADAM10, BACE and PS1, with some modifications in amyloidogenic pathway but without increased amount of Aß peptides. In hypothyroid model, molecular results suggests that adult onset-hypothyroidism may induce the amyloidogenic pathway of APP processing by increasing activity of ß and ?secretases and levels of amyloid peptides mainly in hippocampus. Together these data argue for the idea that hypoactivity of retinoid signalling which occurs naturally with aging could be a factor participating in accelerating aging and that hypothyroidism that become more prevalent with advancing age, could increase, via a hyposignaling of T3 pathway, the vulnerability of amyloidogenic pathway of APP processing as well as of other clinical symptoms of AD

Diseases associated with amyloid aggregation have been a growing focus of medical research in recent years. Altered conformations of amyloidogenic peptides assemble to form soluble aggregates that deposit into the brain and spleen causing disorders such as Alzheimer's disease and Type II diabetes. Emergent theories predict that fibrils may not be the toxic form of amyloidogenic structures and that smaller oligomer and protofibril aggregates may be the primary source of cellular function damage. Studies show that these amyloidogenic aggregates are characterized by an increased number of poorly dehydrated hydrogen backbones and large surface densities of patches of bulk like water which favor protein association. When proteins aggregate to form larger structures, there is a redistribution of water surrounding these proteins. The water dynamics of amyloidogenic aggregation is different than the monomeric form and has a decrease in the number of patches occupied by molecules with bulk-like water behavior. We demonstrate that the redistribution of water during amyloid aggregation is reflected in a change in the dielectric relaxation signal of protein-solvent mixtures. We use dielectric relaxation spectroscopy (DRS) as a tool for studying the dynamics of amyloidogenic peptides--amyloid beta (Ab 1-42) and human islet amyloid polypeptide (hIAPP)--during self-assembly and aggregation. Non-amyloidogenic analogs-- scrambled (Ab 42-1) and rat islet amyloid polypeptide (rIAPP)--were used as controls. We first present studies of amyloidogenic peptides in a deionized water buffer at room temperature as a function of concentration and incubation time. From this we were able to determine differences in amyloidogenic and non-amyloidogenic peptides through the dielectric modulus. We next present the same analytes in a deionized water-glycerol buffer to facilitate the study of the dielectric permittivity at sub-freezing temperatures and model the kinetics of the alpha- and beta- relaxation processes. We conclude our work by studying the peptides in a bovine serum albumin (BSA) and glycerol buffer to demonstrate dielectric spectroscopy as a sensitive tool for measuring amyloidogenic peptides in an in vivo- like condition.