The immunosuppressant rapamycin exacerbates neurotoxicity of Aβ peptide

Lafay-Chebassier, Claire; Pérault-Pochat, Marie Christine; Page, Guylène; Bilan, Agnès Rioux; Damjanac, Milena; Pain, Stéphanie; Houeto, Jean‐Luc; Gil, Roger; Hugon, Jacques

doi:10.1002/jnr.21039

Cited by 48 publications

(48 citation statements)

References 37 publications

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“…It is clear, however, that the role of mTOR in AD is very complex; although it is established that in human AD brains mTOR signaling is increased, especially in neurons predicted to develop Tau pathology, diverging results have been published on the effects of A␤ on mTOR signaling in cell lines. For example, A␤ application to differentiated N2A neuroblastoma cells following 10% serum deprivation significantly decreases the levels of phosphorylated p70S6K (64), whereas differentiated human SH-SY5Y cells exposed to A␤42 show an increase in phosphorylation levels of p70S6K (65). Our data showing an increase in p70S6K phosphorylation in 7PA2 cells are consistent with the latter but appear to be conflicting with the effects of A␤ on N2A cells.…”

Section: Discussionsupporting

confidence: 66%

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Caccamo

Majumder

Richardson

et al. 2010

Journal of Biological Chemistry

762

637

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Accumulation of amyloid-␤ (A␤) and Tau is an invariant feature of Alzheimer disease (AD). The upstream role of A␤ accumulation in the disease pathogenesis is widely accepted, and there is strong evidence showing that A␤ accumulation causes cognitive impairments. However, the molecular mechanisms linking A␤ to cognitive decline remain to be elucidated. Here we show that the buildup of A␤ increases the mammalian target of rapamycin (mTOR) signaling, whereas decreasing mTOR signaling reduces A␤ levels, thereby highlighting an interrelation between mTOR signaling and A␤. The mTOR pathway plays a central role in controlling protein homeostasis and hence, neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates A␤ and Tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycinmediated reduction in A␤ levels. The results presented here provide a molecular basis for the A␤-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces A␤ and Tau pathology. Neurofibrillary tangles (NFTs)2 and amyloid plaques represent the two major hallmark neuropathological lesions of AD (1). NFTs are intraneuronal inclusions that are mainly formed of the hyperphosphorylated microtubule-binding protein Tau (2-5). In contrast, amyloid plaques accumulate extracellularly and are mainly composed of a peptide called amyloid-␤ (A␤) (6, 7). Although the key role of A␤ accumulation in the pathogenesis of AD is widely accepted, the molecular pathways by which A␤ accumulation leads to cognitive decline and Tau pathology remain to be elucidated.The mammalian target of rapamycin (mTOR) is a conserved Ser/Thr kinase that forms two multiprotein complexes known as mTOR complex (mTORC) 1 and 2 (8). mTORC1 controls cellular homeostasis, and its activity is inhibited by rapamycin; in contrast mTORC2 is insensitive to rapamycin and controls cellular shape by modulating actin function (8, 9). By regulating both protein synthesis and degradation, mTOR plays a key role in controlling protein homeostasis and hence brain function; indeed, mTOR activity has been directly linked to learning and memory (10 -13). Additionally, genetic and pharmacological reduction of mTOR activity has been shown to increase the lifespan in different organisms including yeast, Drosophila, and mice (14 -19).mTOR is an inhibitor of macroautophagy, which is a conserved intracellular system designed for the degradation of long-lived proteins and organelles in lysosomes (20 -22). Cumulative evidence suggests that an age-dependent decrease in the autophagy/lysosome system may account for the accumulation of abnormal proteins during aging (23). Macroautophagy (herein referred to as autophagy) is induced when an isolation membrane is generated surrounding cytosolic components, forming an autopha...

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Section: Discussionsupporting

confidence: 66%

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Caccamo

Majumder

Richardson

et al. 2010

Journal of Biological Chemistry

762

637

View full text Add to dashboard Cite

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“…Furthermore, it was revealed that the decrease in p-Akt occurred in brains from rats with type 2 diabetes; a disease that disrupts the common cellular and molecular pathways associated with AD (Correia et al 2012; Yang et al 2013). In addition, Aβ could cause reductions in mTOR phosphorylation at the Ser2448 site (Lafay-Chebassier et al 2005, 2006). The findings are consistent with our observations that the astrocytes exhibited a striking loss of p-Akt at Ser473 and p-mTOR at Ser2448 (Figs.…”

Section: Discussionmentioning

confidence: 99%

Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

Han

Yang

et al. 2015

Cell Mol Neurobiol

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The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), mostly located on astrocytes, are the main mediators for glutamate clearance in humans. Malfunctions of these transporters may lead to excessive glutamate accumulation and subsequent excitotoxicity to neurons, which has been implicated in many kinds of neurodegenerative disorders including Alzheimer’s disease (AD). Yet, the specific mechanism of the glutamate system dysregulation remains vague. To explore whether the insulin/protein kinase B (Akt)/EAAT signaling in human astrocytes could be disturbed by beta-amyloid protein (Aβ) and be protected by insulin, we incubated HA-1800 cells with varying concentrations of Aβ1–42 oligomers and insulin. Then the alterations of several key substrates in this signal transduction pathway were determined. Our results showed that expressions of insulin receptor, phospho-insulin receptor, phospho-protein kinase B, phospho-mammalian target of rapamycin, and EAAT1 and EAAT2 were decreased by the Aβ1–42 oligomers in a dose-dependent manner (p < 0.05) and this trend could be recovered by insulin treatment (p < 0.05). However, the expressions of total Akt and mTOR were invariant (p > 0.05), and the mRNA levels of EAAT1 and EAAT2 were also unchanged (p > 0.05). Taken together, this study indicates that Aβ1–42 oligomers could cause disturbances in insulin/Akt/EAAT signaling in astrocytes, which might be responsible for AD onset and progression. Additionally, insulin can exert protective functions to the brain by modulating protein modifications or expressions.

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“…Studies have shown the beneficial effects of autophagy activation on reducing the accumulation of polyglutamine expansions and ␣-synuclein and on ameliorating disease-associated pathology (52)(53)(54). However, the role of autophagy in AD is controversial (55)(56)(57)(58)(59)(60)(61). Several studies reported that increasing autophagy showed the rescue effects when AD mice were administered rapamycin prior to the development of AD pathology (58,60,61) but had no effect on mice with already established AD-like pathology and cognitive deficits (60).…”

Section: Regulation Of Bace1 Degradationmentioning

confidence: 99%

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

Feng¹,

Tammineni²,

Agrawal

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartino ␤-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for amyloid-␤ generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation. Here, we report that induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition. A significant portion of BACE1 is recruited to the autophagy pathway and co-migrates robustly with autophagic vacuoles along axons. Moreover, we reveal that autophagic vacuole-associated BACE1 is accumulated in the distal axon of Alzheimer's disease-related mutant human APP transgenic neurons and mouse brains. Inducing autophagy in mutant human APP neurons augments autophagic retention of BACE1 in distal axons, leading to enhanced ␤-cleavage of APP. This phenotype can be reversed by Snapin-enhanced retrograde transport, which facilitates BACE1 trafficking to lysosomes for degradation. Therefore, our study provides new insights into autophagy-mediated regulation of BACE1 turnover and APP processing, thus building a foundation for future development of potential Alzheimer's disease therapeutic strategies.Accumulation of senile plaques is a pathological hallmark of Alzheimer's disease (AD).3 Amyloid-␤ (A␤) peptide is the main constituent of senile plaques and is derived from a sequential proteolysis of amyloid precursor protein (APP) by ␤-and ␥-secretases. ␤-Secretase is the initial and rate-limiting enzyme of this process (1-4). ␤-Site APP-cleaving enzyme 1 (BACE1) is the major neuronal ␤-secretase for A␤ generation (1-4). BACE1 levels increase with age (5) and are elevated in AD patient brains (6), thereby making BACE1 a prime target for therapeutic intervention (7-9). BACE1 is synthesized in the endoplasmic reticulum and then delivered to the cell surface from the trans-Golgi network (TGN). Mature BACE1 traffics to endosomes via internalization from the plasma membrane or directly from the TGN (3, 10 -12). The endosomal compartments (especially late endosomes (LEs) or multivesicular bodies) provide an acidic environment that is crucial for optimal ␤-secretase activity (10, 13-17), whereas BACE1 is ultimately degraded within lysosomes (15, 18 -20). Given that mature lysosomes are mainly located in the soma of neurons (21-24), proper retrograde transport of LE-loaded BACE1 is critical for the trafficking of BACE1 to lysosomes for turnover (20).Autophagy is the major cellular degradation pathway for long-lived proteins and damaged organelles (25-28). Altered autophagy has been linked to several major age-related neurodegenerative diseases, including AD (27). Recent studies established that autophagosomes are continuously...

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The immunosuppressant rapamycin exacerbates neurotoxicity of Aβ peptide

Cited by 48 publications

References 37 publications

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Molecular Interplay between Mammalian Target of Rapamycin (mTOR), Amyloid-β, and Tau

Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

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