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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    • "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.
    Neurobiology of Disease 03/2015; 101. DOI:10.1016/j.nbd.2015.03.014 · 5.08 Impact Factor
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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.
    Neuron 10/2014; 84(2):275-291. DOI:10.1016/j.neuron.2014.09.034 · 15.05 Impact Factor
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    • "The mammalian target of rapamycin (mTOR) pathway plays a major role in receiving autophagic stimuli with its ability to sense nutrient and metabolic hormonal signals to initiate autophagy (Cai et al., 2012). The mTOR-dependent signaling pathway seems to be involved in AD patients' brains as well as in AD models (Li et al., 2005; Pei and Hugon, 2008). Enhanced mTOR signaling activity increases Ab deposits and NFTs formation in AD (Lafay-Chebassier et al., 2005). "
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    ABSTRACT: Alzheimer's disease (AD) is an age-related devastating neurodegenerative disorder, which severely impacts on the global economic development and healthcare system. Though AD has been studied for more than 100 years since 1906, the exact cause(s) and pathogenic mechanism(s) remain to be clarified. Also, the efficient disease- modifying treatment and ideal diagnostic method for AD are unavailable. Perturbed cerebral glucose metabolism, an invariant pathophysiological feature of AD, may be a critical contributor to the pathogenesis of this disease. In this review, we firstly discussed the features of cerebral glucose metabolism in physiological and pathological conditions. Then, we further reviewed the contribution of glucose transportation abnormality and intracellular glucose catabolism dysfunction in AD pathophysiology, and proposed a hypothesis that multiple pathogenic cascades induced by impaired cerebral glucose metabolism could result in neuronal degeneration and consequently cognitive deficits in AD patients. Among these pathogenic processes, altered functional status of thiamine metabolism and brain insulin resistance are highly emphasized and characterized as major pathogenic mechanisms. Finally, considering the fact that AD patients exhibit cerebral glucose hypometabolism possibly due to impairments of insulin signaling and altered thiamine metabolism, we also discuss some potential possibilities to uncover diagnostic biomarkers for AD from abnormal glucose metabolism and to develop drugs targeting at repairing insulin signaling impairment and correcting thiamine metabolism abnormality. We conclude that glucose metabolism abnormality plays a critical role in AD pathophysiological alterations through the induction of multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, and so forth. To clarify the causes, pathogeneses and consequences of cerebral hypometabolism in AD will help break the bottleneck of current AD study in finding ideal diagnostic biomarker and disease-modifying therapy.
    Progress in Neurobiology 07/2013; 108. DOI:10.1016/j.pneurobio.2013.06.004 · 9.99 Impact Factor
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