mTOR‐dependent signalling in Alzheimer's disease

Pei, Jin-Jing; Hugon, Jacques

doi:10.1111/j.1582-4934.2008.00509.x

Cited by 179 publications

(137 citation statements)

References 68 publications

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“…3, G-I). Taken together, these results strongly suggest that the build-up of A␤ increases mTOR signaling and, more importantly, are consistent with reports showing an increase in mTOR signaling in human brains affected by AD (47)(48)(49)(50)(51).…”

Section: Resultssupporting

confidence: 80%

“…Along these lines, Wyss-Coray and colleagues (60) showed that increasing autophagy by overexpressing beclin-1, a key protein involved in autophagy induction, reduces A␤ deposits in a transgenic model of AD. To complicate this apparent contradiction, it has been shown that mTOR function, which negatively regulates autophagy, is increased in selected neurons of AD brains that are predicted to develop Tau pathology, suggesting that chronic high levels of mTOR signaling (and hence low levels of autophagy) may be detrimental in AD brains (47)(48)(49)(50)(51). Our data support the theory that an increase in autophagy may have a beneficial effect on AD pathogenesis.…”

Section: Discussionsupporting

confidence: 78%

“…All these findings are consistent with the idea that different stressors may have opposite effects on mTOR in different cells or cell types, some of which may undergo cell death and some neurofibrillary degeneration (reviewed in Ref. 51).…”

Section: Discussionsupporting

confidence: 77%

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

Caccamo

Majumder

Richardson

et al. 2010

Journal of Biological Chemistry

783

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: Resultssupporting

confidence: 80%

Section: Discussionsupporting

confidence: 78%

See 1 more Smart Citation

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

Caccamo

Majumder

Richardson

et al. 2010

Journal of Biological Chemistry

783

637

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“…Evidence from aged and AD brains shows that mTOR signaling is selectively increased in neurons that are likely to develop neurofibrillary tangles and that such an increase correlates with tau phosphorylation [132,133]. This evidence has led to the hypothesis that the chronic increase in mTOR function that occurs during aging may facilitate the development of tau pathology.…”

Section: Undetermined Pathways In Samp8 That Could Addmentioning

confidence: 99%

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Pallàs

2012

ISRN Cell Biology

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The causes of aging remain unknown, but they are probably intimately linked to a multifactorial process that affects cell networks to varying degrees. Although a growing number of aging and Alzheimer's disease (AD) animal models are available, a more comprehensive and physiological mouse model is required. In this context, the senescence-accelerated mouse prone 8 (SAMP8) has a number of advantages, since its rapid physiological senescence means that it has about half the normal lifespan of a rodent. In addition, according to data gathered over the last five years, some of its behavioral traits and histopathology resemble AD human dementia. SAMP8 has remarkable pathological similarities to AD and may prove to be an excellent model for acquiring more in-depth knowledge of the age-related neurodegenerative processes behind brain senescence and AD in particular. We review these facts and particularly the data on parameters related to neurodegeneration. SAMP8 also shows signs of aging in the immune, vascular, and metabolic systems, among others.

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“…insulin/insulin-like growth factor, cell energy status, nutrients, and stress) via different signaling transduction pathways (11), some of which are modulated by A␤ (20 -24). Indeed, evidence from AD brains shows that mTOR signaling is selectively increased in neurons predicted to develop neurofibrillary tangles and that such an increase correlates with Tau phosphorylation (25)(26)(27)(28). This evidence has led to the hypothesis that the chronic increase in mTOR function occurring during aging may facilitate the development of Tau pathology (27).…”

mentioning

confidence: 99%

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

Caccamo¹,

Maldonado²,

Majumder³

et al. 2011

Journal of Biological Chemistry

161

132

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Reducing the mammalian target of rapamycin (mTOR) activity increases lifespan and health span in a variety of organisms. Alterations in protein homeostasis and mTOR activity and signaling have been reported in several neurodegenerative disorders, including Alzheimer disease (AD); however, the causes of such deregulations remain elusive. Here, we show that mTOR activity and signaling are increased in cell lines stably transfected with mutant amyloid precursor protein (APP) and in brains of 3xTg-AD mice, an animal model of AD. In addition, we show that in the 3xTg-AD mice, mTOR activity can be reduced to wild type levels by genetically preventing A␤ accumulation. Similarly, intrahippocampal injections of an anti-A␤ antibody reduced A␤ levels and normalized mTOR activity, indicating that high A␤ levels are necessary for mTOR hyperactivity in 3xTg-AD mice. We also show that the intrahippocampal injection of naturally secreted A␤ is sufficient to increase mTOR signaling in the brains of wild type mice. The mechanism behind the A␤-induced mTOR hyperactivity is mediated by the proline-rich Akt substrate 40 (PRAS40) as we show that the activation of PRAS40 plays a key role in the A␤-induced mTOR hyperactivity. Taken together, our data show that A␤ accumulation, which has been suggested to be the culprit of AD pathogenesis, causes mTOR hyperactivity by regulating PRAS40 phosphorylation. These data further indicate that the mTOR pathway is one of the pathways by which A␤ exerts its toxicity and further support the idea that reducing mTOR signaling in AD may be a valid therapeutic approach.Amyloid plaques and neurofibrillary tangles are hallmark neuropathological lesions of Alzheimer disease (AD), 3 the most common form of neurodegenerative disorder (1). Neurofibrillary tangles are intracellular inclusions formed of hyperphosphorylated Tau (2-4). Plaques are extracellular inclusions mainly formed of a small peptide called amyloid-␤ (A␤) (5, 6). Clinically, AD is characterized by profound memory loss and cognitive dysfunction (7). Growing evidence is converging on soluble A␤ as a mediator of early cognitive decline in AD (8, 9). Although the molecular mechanisms underlying A␤-induced cognitive decline remain elusive, soluble A␤ oligomers have been shown to alter signal transduction pathways that are key for learning and memory, suggesting that alterations in such pathways may underlie the onset of cognitive decline in AD (10).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 (11). mTORC1 controls protein homeostasis; its activity is inhibited by rapamycin, and it contains mTOR, raptor, proline-rich Akt substrate 40 kDa (PRAS40), and mLT8. mTORC2, which is insensitive to rapamycin, controls cellular shape by modulating actin function and contains mTOR, rictor, mLST8, and hSIN (11, 12). In mTORC1, raptor binds to mTOR substrates and is necessary for mTOR activity (13). PRAS40 is another mTOR regulatory protein, which inhibits mTOR...

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mTOR‐dependent signalling in Alzheimer's disease

Cited by 179 publications

References 68 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

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Naturally Secreted Amyloid-β Increases Mammalian Target of Rapamycin (mTOR) Activity via a PRAS40-mediated Mechanism

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