Modulation of mTOR function to increase autophagy and inhibit apoptosis is involved in the protective effects of pharmacologic agents targeting diabetes and Alzheimer's disease (AD).
As examples, the role of phosphoinositide 3 kinase/Akt/ mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway in cell cycle re-entry and blocking autophagy are discussed as potential common intracellular components between AD and cancer pathogenesis, with diverse clinical diagnosis.
Moreover, the everolimus-induced mTOR inhibition reduced human APP/Aβ and human tau levels and improved cognitive function and depressive-like phenotype in the 3 × Tg-AD mice.
We reassess literature described by a recent perspective article calling for the use of MTOR inhibition in dementia and conclude that rapamycin could be useful, but only in people who are in the earliest stages of Alzheimer disease.
The pathways of mTOR and SIRT1 are closely integrated. mTOR forms the complexes mTOR Complex 1 and mTOR Complex 2 and can impact multiple neurodegenerative disorders that include Alzheimer's disease, Huntington's disease, and Parkinson's disease.
It was also observed that amyloid precursor protein, ryanodine receptor, mammalian target of rapamycin complex 1, and receptor for advanced glycation end products are associated with a worse prognosis in AD.
In the present study, we examine how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactive mammalian target of rapamycin (mTOR) activity, affects the hippocampal protein levels of key neuropathological hallmarks of AD.
NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer's disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.
Collectively, our results demonstrate that rapamycin-independent blocking of mTOR enhances p-tau (Ser<sup>396</sup>) in a PI3K-dependent way, suggesting the careful consideration of future therapeutic approaches for AD, which will be based on mTOR inhibition.
While the inhibitory link between AMPK and mTOR seems to be disrupted, we suggest oxidative stress as the underlying mechanism for concurrent activation of AMPK and mTOR in AD.
Taken together, our data suggest that ADDL-induced abnormal autophagy is correlated with Aβ aggregation degree and the MTOR pathway, which might contribute to ADDL-induced AD pathogenesis.
In the central nervous system, mTOR inhibition demonstrates neuroprotective patterns in aging and Alzheimer's disease (AD) by preserving mitochondrial function and reducing amyloid beta retention.
This review discusses recent research highlighting the complex role of mTOR associated with the presence of two hallmarks of AD pathology, senile plaques (composed mostly of fibrillar Aß peptides), and NFT (composed mostly of hyperphosphorylated tau protein).
Age-related exacerbations involve the number of components affected in the mechanistic target of rapamycin pathway, the levels of components of the mitogen-activated protein kinase pathway, and proteins associated with Alzheimer's disease.
Because mechanistic target of rapamycin (mTOR) negatively regulates autophagy and is hyperactive in the brains of patients with AD, mTOR is an attractive therapeutic target for AD.
Mammalian target of rapamycin (mTOR), which is aberrantly activated in AD since early stages, plays a key role during AD neurodegeneration by, on one side, inhibiting insulin signaling as a negative feedback mechanism and, on the other side, regulating protein homeostasis (synthesis/clearance).
The mammalian target of rapamycin complex 1 (mTORC1), which was found to be hyperactive in AD brain, regulates autophagy and is considered to be mechanistically important to aberrant autophagy in AD.
Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK.