Up-Regulation of Phosphorylated/Activated p70 S6 Kinase and Its Relationship to Neurofibrillary Pathology in Alzheimer's Disease

An, Wenlin; Cowburn, Richard F.; Lin, Li; Braak, Heiko; Alafuzoff, Irina; Iqbal, Khalid; Iqbal, Inge-Grundke; Winblad, Bengt; Pei, Jin-Jing

doi:10.1016/s0002-9440(10)63687-5

Cited by 291 publications

(281 citation statements)

References 81 publications

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“…For example, PI3K/mTOR signaling regulates Tau phosphorylation (24), and mTOR activation enhances Tau-induced neurodegeneration in a Drosophila model of tauopathies (78). Further strengthening the mTOR/Tau link are the data resulting from investigations of AD brains showing 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).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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confidence: 99%

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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

162

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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Section: Discussionmentioning

confidence: 99%

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

162

132

View full text Add to dashboard Cite

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“…In both of these conceptual models, mTORC1 signaling in the aged may drive much of the pathophysiology of aging. While it is not clear that increased mTORC1 signaling inevitably accelerates aging, increased mTORC1 signaling is associated with numerous age‐related diseases and pathologies, including Alzheimer's disease (An et al ., 2003), diabetes (Inoki et al ., 2011; Volkers et al ., 2014), and cancer (Bar‐Peled et al ., 2013; Grabiner et al ., 2014). Increased mTORC1 signaling is found in human cells and certain animal models of Hutchinson–Gilford progeria syndrome, a rare, fatal genetic disorder characterized by the early onset of conditions associated with old age (Cao et al ., 2011; Ramos et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

et al. 2015

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SummaryInhibition of the mTOR (mechanistic Target Of Rapamycin) signaling pathway robustly extends the lifespan of model organisms including mice. The precise molecular mechanisms and physiological effects that underlie the beneficial effects of rapamycin are an exciting area of research. Surprisingly, while some data suggest that mTOR signaling normally increases with age in mice, the effect of age on mTOR signaling has never been comprehensively assessed. Here, we determine the age‐associated changes in mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2) signaling in the liver, muscle, adipose, and heart of C57BL/6J.Nia mice, the lifespan of which can be extended by rapamycin treatment. We find that the effect of age on several different readouts of mTORC1 and mTORC2 activity varies by tissue and sex in C57BL/6J.Nia mice. Intriguingly, we observed increased mTORC1 activity in the liver and heart tissue of young female mice compared to male mice of the same age. Tissue and substrate‐specific results were observed in the livers of HET3 and DBA/2 mouse strains, and in liver, muscle and adipose tissue of F344 rats. Our results demonstrate that aging does not result in increased mTOR signaling in most tissues and suggest that rapamycin does not promote lifespan by reversing or blunting such an effect.

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“…Zinc, which is highly concentrated in synaptic vesicles in the mossy fiber zone of the hippocampus and may also be involved in AD pathogenesis (54), can activate some of these kinases, including Erk (55)(56)(57)(58)(59)(60)(61)(62). How apoE4 stimulates tau phosphorylation is largely unknown.…”

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confidence: 99%

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

Harris

Brecht

et al. 2004

Journal of Biological Chemistry

145

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Although apolipoprotein (apo) E4 is present in amyloid plaques and neurofibrillary tangles, its pathogenic role in Alzheimer's disease (AD) is unclear. Neuronal expression of apoE4 or apoE4 fragments in transgenic mice increases tau phosphorylation. To identify the kinase responsible for the increase, we studied transgenic mice expressing human apoE3 or apoE4 in neurons under the control of the neuron-specific enolase promoter. Brain levels of phosphorylated tau (p-tau) and phosphorylated (active) extracellular signal-regulated kinase (pErk) increased with age in both groups but were considerably higher in the apoE4 mice. Other candidate kinases, including glycogen synthase kinase 3␤ and cyclin-dependent kinase-5 and its activators p25 and p35, were not significantly altered. The increases in p-Erk and p-tau were highest in the hippocampus, intermediate in the cortex, and lowest in the cerebellum. In the hippocampus, p-Erk and p-tau accumulated in the hilus and CA3 region of the dentate gyrus, where high levels of zinc are found along mossy fibers. In Neuro-2a cells stably expressing apoE3 or apoE4, treatment with ZnCl 2 generated 2-fold more p-Erk and 3-fold more p-tau in the apoE4-expressing cells. Phosphorylation of Erk and tau was reduced by preincubation with the Erk pathway inhibitor U0126. Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD.Human apolipoprotein (apo) 1 E4 has been identified as a major risk factor for Alzheimer's disease (AD) (1, 2). It increases the occurrence and lowers the age of onset of AD and is associated with ϳ40 -65% of cases of sporadic and familial AD (1, 2). The neuropathological hallmarks of AD are neuritic amyloid plaques and neurofibrillary tangles (NFTs) in the brain (3-5). The plaques are extracellular deposits consisting primarily of amyloid-beta (A␤) peptides (3-5), the proteolytic products of the amyloid protein precursor. NFTs are primarily intracellular deposits composed largely of highly phosphorylated tau (p-tau), a microtubule-associated protein (4), as well as phosphorylated neurofilaments of high molecular weight (6, 7). Both plaques and NFTs contain apoE (8 -10), but the role of apoE in the pathogenesis of these lesions is unclear.Several hypotheses have been proposed to explain the association of apoE4 with AD (10 -14). They include modulation of the deposition and clearance of A␤ peptides and the formation of plaques (15-21), impairment of the antioxidative defense system (22), dysregulation of neuronal signaling pathways (23), altered phosphorylation of tau and NFT formation (24 -29), depletion of cytosolic androgen receptor levels in the brain (30, 31), potentiation of A␤-induced lysosomal leakage and apoptosis in neuronal cells (32), and promotion of endosomal abnormalities linked to A␤ overproduction (33-35). However, the mechanisms of these apoE4-mediated detrimental effects are largely unknown, ...

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Up-Regulation of Phosphorylated/Activated p70 S6 Kinase and Its Relationship to Neurofibrillary Pathology in Alzheimer's Disease

Cited by 291 publications

References 81 publications

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

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

Sex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice

Increased tau Phosphorylation in Apolipoprotein E4 Transgenic Mice Is Associated with Activation of Extracellular Signal-regulated Kinase

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