Mammalian target of rapamycin: A valid therapeutic target through the autophagy pathway for alzheimer's disease?

Cai, Zhiyou; Zhao, Bin; Li, Keshen; Zhang, Liangqing; Li, Chunhua; Quazi, Sohel H.; Yan, Tingyu

doi:10.1002/jnr.23011

Cited by 126 publications

(101 citation statements)

References 166 publications

(212 reference statements)

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“…CDK5 and the mTOR-signaling pathways, which are known to be activated in FCD II and TSC [but not in FCD I (28); for a review, see (9,20)], have been implicated in the mechanisms underlying cellular aging and neurodegeneration, including tau hyperphosphorylation (1,17,31,37,42,44,48). Interestingly, tau-positive neuropil threads were often observed in cortical regions with prominent IR for pS6 (used as marker of mTOR pathway activation) and hyperphosphorylated tau was detected in pS6-positive dysmorphic neurons.…”

Section: Expression Pattern Of Neurodegenerationrelated Proteins In Fmentioning

confidence: 99%

Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

et al. 2013

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Several lines of evidence suggest that cell injury may occur in malformations of cortical development associated with epilepsy. Moreover, recent studies support the link between neurodevelopmental and neurodegenerative mechanisms. We evaluated a series of focal cortical dysplasia (FCD, n=26; type I and II) and tuberous sclerosis complex (TSC, n=6) cases. Sections were processed for terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick-end labeling (TUNEL) labeling and immunohistochemistry using markers for the evaluation of apoptosis signaling pathways and neurodegeneration-related proteins/pathways. In both FCD II and TSC specimens, we observed significant increases in both TUNEL-positive and caspase-3-positive cells compared with controls and FCD I. Expression of β-amyloid precursor protein was observed in neuronal soma and processes in FCD II and TSC. In these specimens, we also observed an abnormal expression of death receptor-6. Immunoreactivity for phosphorylated tau was only found in older patients with FCD II and TSC. In these cases, prominent nuclear/cytoplasmic p62 immunoreactivity was detected in both dysmorphic neurons and balloon/giant cells. Our data provide evidence of complex, but similar, mechanisms of cell injury in focal malformations of cortical development associated with mammalian target of rapamycin pathway hyperactivation, with prominent induction of apoptosis-signaling pathways and premature activation of mechanisms of neurodegeneration.

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Section: Expression Pattern Of Neurodegenerationrelated Proteins In Fmentioning

confidence: 99%

Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

et al. 2013

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“…Indeed, dysfunction of the autophagy-lysosomal system also contributes to Aβ accumulation, the formation of tau oligomers, and insoluble aggregates, and in contrast induction of autophagy enhances the clearance of both soluble and aggregated forms of Aβ and tau proteins [17]. …”

Section: Introductionmentioning

confidence: 99%

Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

Perluigi

Pupo

Tramutola

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

144

118

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability characterized by the presence of three copies of chromosome 21 (Chr21). Individuals with DS have sufficient neuropathology for a diagnosis of Alzheimer's disease (AD) after the age of 40 years. The aim of our study is to gain new insights in the molecular mechanisms impaired in DS subjects that eventually lead to the development of dementia. We evaluate the PI3K/Akt/mTOR axis in the frontal cortex from DS cases (under the age of 40 years) and DS with AD neuropathology compared with age-matched controls (Young and Old). The PI3K/Akt/mTOR axis may control several key pathways involved in AD that, if aberrantly regulated, affect amyloid beta (Aβ) deposition and tau phosphorylation. Our results show a hyperactivation of PI3K/Akt/mTOR axis in individuals with DS, with and without AD pathology, in comparison with respective controls. The PI3K/Akt/mTOR de-regulation results in decreased autophagy, inhibition of IRS1 and GSK3β activity. Moreover, our data suggest that aberrant activation of the PI3K/Akt/mTOR axis acts in parallel to RCAN1 in phosphorylating tau, in DS and DS/AD. In conclusion, this study provides insights into the neuropathological mechanisms that may be engaged during the development of AD in DS. We suggest that deregulation of this signaling cascade is already evident in young DS cases and persist in the presence of AD pathology. The impairment of the PI3K/Akt/mTOR axis in DS population might represent a key-contributing factor to the neurodegenerative process that culminates in Alzheimer-like dementia.

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“…How stimulating the UPR and autophagy can promote neuronal cell survival is an issue that has received much attention [1,74]. In the context of AD, Bip can bind to nascent APP and facilitate its correct folding, which would limit Ab42 peptide production and accumulation in the cell, thereby promoting neuronal survival [75].…”

Section: Discussionmentioning

confidence: 99%

The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease

et al. 2015

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The unfolded protein response (UPR) and autophagy are two cellular processes involved in the clearing of intracellular misfolded proteins. Both pathways are targets for molecules that may serve as treatments for several diseases, including neurodegenerative disorders like Alzheimer's disease (AD). In the present work, we show that 2-hydroxy-DHA (HDHA), a docosahexaenoic acid (DHA) derivate that restores cognitive function in a transgenic mouse model of AD, modulates UPR and autophagy in differentiated neuron-like SH-SY5Y cells. Mild therapeutic HDHA exposure induced UPR activation, characterized by the up-regulation of the molecular chaperone Bip as well as PERK-mediated stimulation of eIF2α phosphorylation. Key proteins involved in initiating autophagy, such as beclin-1, and several Atg proteins involved in autophagosome maturation (Atg3, Atg5, Atg12 and Atg7), were also up-regulated on exposure to HDHA. Moreover, when HDHA-mediated autophagy was studied after amyloid-β peptide (Aβ) stimulation to mimic the neurotoxic environment of AD, it was associated with increased cell survival, suggesting that HDHA driven modulation of this process at least in part mediates the neuroprotective effects of this new anti-neurodegenerative drug. The present results in part explain the pharmacological effects of HDHA inducing full recovery of the cognitive scores in murine models of AD.

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Mammalian target of rapamycin: A valid therapeutic target through the autophagy pathway for alzheimer's disease?

Cited by 126 publications

References 166 publications

Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

Cell injury and Premature Neurodegeneration in Focal Malformations of Cortical Development

Neuropathological role of PI3K/Akt/mTOR axis in Down syndrome brain

The unfolded protein response in the therapeutic effect of hydroxy-DHA against Alzheimer’s disease

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