mTOR in Down syndrome: Role in Ass and tau neuropathology and transition to Alzheimer disease like dementia
ABSTRACT The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation, longevity and cytoskeletal formation. The mTOR pathway represents a key growth and survival pathway involved in several diseases such as cancer, obesity, cardiovascular disease and neurodegenerative diseases. Numerous studies linked the alterations of mTOR pathway to age dependent cognitive decline, pathogenesis of Alzheimer disease (AD) and AD like dementia in Down syndrome (DS) DS is the most frequent chromosomal abnormality that causes intellectual disability. The neuropathology of AD in DS is complex and involves impaired mitochondrial function, defects in neurogenesis, increased oxidative stress, altered proteostasis and autophagy networks as a result of triplication of chromosome 21(chr 21) The chr21 gene products are considered a principal neuropathogenic moiety in DS. Several genes involved respectively in the formation of senile plaques and neurofibrillary tangles (NFT) two main pathological hallmarks of AD, are mapped on chr21. Further, in subjects with DS the activation of mTOR signaling contributes to A&bgr; generation and the formation of NFT. 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) Oxidative stress, associated with chr21 related A&bgr; and mitochondrial alterations, may significantly contribute to this linkage of mTOR to AD like neuropathology in DS. HIGHLIGHTSDown syndrome (DS) brain is under significant oxidative stress induced in part by A&bgr;.At age 40 50 DS persons have Alzheimer disease (AD) like pathology and dementia.mTOR is activated in DS brain, in part by the action of A&bgr; leading to AD pathology.A DS viscous cycle of A&bgr; oxidative stress, mTOR and more A&bgr; and abnormal tau exists.
Free radical biology medicine