mTOR-dependent signalling in Alzheimer's disease

Karolinska Institute, Department of Neurobiology, Care Sciences and Society, KI-ADRC, Stockholm, Sweden.
Journal of Cellular and Molecular Medicine (Impact Factor: 4.01). 01/2009; 12(6B):2525-32. DOI: 10.1111/j.1582-4934.2008.00509.x
Source: PubMed


Neurodegeneration and neurofibrillary degeneration are the two main pathological mechanisms of cognitive impairments in Alzheimer's disease (AD). It is not clear what factors determine the fates of neurons during the progress of the disease. Emerging evidence has suggested that mTOR-dependent signalling is involved in the two types of degeneration in AD brains. This review focuses on the roles of mTOR-dependent signalling in the pathogenesis of AD. It summarizes the recent advancements in the understanding of its roles in neurodegeneration and neurofibrillary degeneration, as well as the evidence achieved when mTOR-related signalling components were tested as potential biomarkers of cognitive impairments in the clinical diagnosis of AD.

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    • "According to recent reports, mTOR was hyperactivated in an Alzheimer's animal model. This hyperactivity of mTOR was deeply involved in hyperphosphorylation of Aβ and tau [17] [18] [19] [20]. In other words, it was reported that hyperactivation of mTOR reduced autophagy and directly contributed to hyperphosphorylation and aggregation of tau proteins [21] [22]. "
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    ABSTRACT: Purpose: Neurofibrillary tangles, one of pathological features of Alzheimer's disease, are produced by the hyperphosphorylation and aggregation of tau protein. This study aimed to investigate the effects of treadmill exercise on PI3K/AKT/mTOR signal transmission, autophagy, and cognitive ability that are involved in the hyperphosphorylation and aggregation of tau protein. Methods: Experimental animals (NSE/htau23 mice) were divided into non-transgenic control group (Non-Tg-Control; CON; n = 7), transgenic control group (Tg-CON; n = 7), and transgenic exercise group (Tg-Treadmill Exercise; TE; n = 7). The Tg-TE group was subjected to treadmill exercise for 12 weeks. After the treadmill exercise was completed, the cognitive ability was determined by conducting underwater maze tests. Western blot was conducted to determine the phosphorylation status of PI3K/AKT/mTOR proteins and autophagy-related proteins (Beclin-1, p62, LC3-B); hyperphosphorylation and aggregation of tau protein (Ser199/202, Ser404, Thr231, PHF-1); and phosphorylation of GSK-3β, which is involved in the phosphorylation of tau protein in the cerebral cortex of experimental animals. Results: In the Tg-TE group that was subjected to treadmill exercise for 12 weeks, abnormal mTOR phosphorylation of PI3K/AKT proteins was improved via increased phosphorylation and its activity was inhibited by increased GSK-3β phosphorylation compared with those in the Tg-CON group, which was used as the control group. In addition, the expression of Beclin-1 protein involved in autophagosome formation was increased in the Tg-TE group compared with that in the Tg-CON group, whereas that of p62 protein was reduced in the Tg-TE group compared with that in the Tg-CON group. Autophagy was activated owing to the increased expression of LC3-B that controls the completion of autophagosome formation. The hyperphosphorylation and aggregation (Ser199/202, Ser404, Thr231, PHF-1) of tau protein was found to be reduced in the Tg-TE group compared with that in the Tg-CON group. Furthermore, in the underwater maze test, the Tg-TE group showed a reduced escape time and distance compared with those of the Tg-CON group, suggesting that learning and cognitive ability were improved. Conclusion: These findings suggest that aerobic exercise such as treadmill exercise might be an effective approach to ameliorate the pathological features (or neurofibrillary tangles) of Alzheimer's disease.
    Full-text · Article · Sep 2015
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    • "In the last decade mTOR signalling has been extensively analysed in AD brain and in AD mouse models demonstrating an aberrant upregulation during the development of the neurodegenerative process (Oddo, 2012; Pei and Hugon, 2008; Richardson et al., 2014). Evidence from post-mortem human AD brains indicates that the levels of phospho-mTOR at Ser-2448 and at Ser-2481, and two of its downstream targets, p70S6K and eIF4E, are increased in hippocampus and in other brain areas (Griffin et al., 2005; Li et al., 2005; Pei and Hugon, 2008; Sun et al., 2014). In addition, mTOR hyperactivity correlated with Braak stages and/or cognitive severity of AD patients. "
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    ABSTRACT: Compelling evidence indicates that the mammalian target of rapamycin (mTOR) signaling pathway is involved in cellular senescence, organismal aging and age-dependent diseases. mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signalling. In multicellular organisms, mTOR regulates cell growth and metabolism in response to nutrients, growth factors and cellular energy conditions. Growing studies highlight that disturbance in mTOR signalling in the brain affects multiple pathways including glucose metabolism, energy production, mitochondrial function, cell growth and autophagy. All these events are key players in age-related cognitive decline such as development of Alzheimer disease (AD). The current review discusses the main regulatory roles of mTOR signalling in the brain, in particular focusing on autophagy, glucose metabolism and mitochondrial functions. Targeting mTOR in the CNS can offer new prospective for drug discovery; however further studies are needed for a comprehensive understanding of mTOR, which lies at the crossroads of multiple signals involved in AD etiology and pathogenesis. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Neurobiology of Disease
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    • "The pathological hallmarks of this disorder are the accumulation of extracellular senile plaques and intracellular neurofibrillary tangles (NFT). The amyloid cascade hypothesis posits that abnormalities in the sequential cleavage of the amyloid precursor protein (APP) by b-secretase and then g-secretase results in the generation of toxic oligomeric Ab species , which initiate a cascade of cellular dysfunction resulting in synaptic and ultimately neuronal loss (reviewed in Pei and Hugon, 2008; Wang et al., 2014). "
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) signaling pathway is a crucial cellular signaling hub that, like the nervous system itself, integrates internal and external cues to elicit critical outputs including growth control, protein synthesis, gene expression, and metabolic balance. The importance of mTOR signaling to brain function is underscored by the myriad disorders in which mTOR pathway dysfunction is implicated, such as autism, epilepsy, and neurodegenerative disorders. Pharmacological manipulation of mTOR signaling holds therapeutic promise and has entered clinical trials for several disorders. Here, we review the functions of mTOR signaling in the normal and pathological brain, highlighting ongoing efforts to translate our understanding of cellular physiology into direct medical benefit for neurological disorders.
    Full-text · Article · Oct 2014 · Neuron
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