Journal
MOLECULAR NEURODEGENERATION
Volume 16, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13024-021-00428-5
Keywords
Alzheimer's; mTOR; Rapamycin; Insulin signaling; Akt; Parkinson's
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Funding
- NIA NIH [AGO44871-01]
- Bennett Foundation
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mTOR is involved in regulating energy metabolism, neuronal growth, insulin signaling, and autophagy, playing both beneficial and pathogenic roles in neurodegenerative diseases. Balanced actions of mTOR complexes may have implications for Alzheimer's disease, Parkinson's disease, Huntington's disease, Frontotemporal dementia, and Amyotrophic Lateral Sclerosis. Beyond rapamycin, rapalogs with improved tolerability and delivery modes hold promise in treating age-related conditions.
Novel targets to arrest neurodegeneration in several dementing conditions involving misfolded protein accumulations may be found in the diverse signaling pathways of the Mammalian/mechanistic target of rapamycin (mTOR). As a nutrient sensor, mTOR has important homeostatic functions to regulate energy metabolism and support neuronal growth and plasticity. However, in Alzheimer's disease (AD), mTOR alternately plays important pathogenic roles by inhibiting both insulin signaling and autophagic removal of beta-amyloid (A beta) and phospho-tau (ptau) aggregates. It also plays a role in the cerebrovascular dysfunction of AD. mTOR is a serine/threonine kinase residing at the core in either of two multiprotein complexes termed mTORC1 and mTORC2. Recent data suggest that their balanced actions also have implications for Parkinson's disease (PD) and Huntington's disease (HD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Beyond rapamycin; an mTOR inhibitor, there are rapalogs having greater tolerability and micro delivery modes, that hold promise in arresting these age dependent conditions.
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