It has also been implicated in Alzheimer's disease (AD) with neuronal cells and hippocampal slices of AD transgenic mice experiencing dysregulated mTOR and synaptic plasticity in response to treatment with the toxic amyloid β (Aβ(1-42)) peptide, which has been implicated in AD.
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.
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).
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.
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.
Moreover, the expression patterns of mTOR components in adult DS hippocampus support its association with Alzheimer disease-related histopathologic changes.
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.
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).
In Alzheimer's disease (AD), the control of translation is dysregulated, precisely, two opposite pathways: double-stranded RNA-dependent protein kinase (PKR) is up-regulated and mammalian target of rapamycin (mTOR) is down-regulated.
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.
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.
There are many similar pathophysiological processes and molecular pathways between Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM), and pharmacologic agents used to treat T2DM, including glucagon-like peptide-1 (GLP-1) analogs, seem to be beneficial for AD. mTOR mediates the effects of GLP-1 analogs in the treatment of T2DM; hence, I hypothesize that mTOR is a key molecule for mediating the protective effects of GLP-1 for 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.
We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1) is dysregulated in cells deficient in presenilin, a protein associated with AD.
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.