Oxidative Stress and mTOR Activation in Down Syndrome Brain: Roles in Aβ42 and Tau Neuropathology and Transition to Alzheimer Disease-Like Dementia

摘要

Down syndrome (DS), the most frequent chromosomal abnormality in humans, results from complete or partial trisomy of chromosome 21 (Chr21). Though there is intellectual disability in DS people from birth, at about 40-50 years of age conversion to Alzheimer disease (AD)-like neuropathology and dementia often occurs. The mammalian target of rapamycin (mTOR), a serine/threonine protein kinase involved in the regulation of protein synthesis and degradation and insulin signaling, among other functions, is implicated in several diseases, including AD. Numerous studies, many from our laboratory, linked activation of the mTOR pathway by, among other means, oxidative stress-associated Aβ42 to age-dependent pathology of AD and AD-like dementia in DS. Several Chr21 gene products are associated with oxidative stress, among which is amyloid precursor protein , the source of Aβ42. Specific genes involved in the formation of AD-related senile plaques (composed mostly of fibrillar Aβ), and neurofibrillary tangles (NFT, composed mostly of hyperphosphorylated tau protein), two main pathological hallmarks of AD, are mapped on Chr21. This presentation highlights our recent research on DS brain using oxidative stress and redox proteomics methods showing activation of mTOR signaling contributes to generation of neurotoxic and oxidative stress-associated Aβ-oligomers (and senile plaques) and the formation of NFT. Thus, a vicious cycle between oxidative stress-related, Aβ-associated mTOR activation and mTOR activation-mediated AD-like pathology and dementia in conversion of DS to DS with AD is present. Identification of potential new therapeutic targets associated with the mTOR pathway to modulate this conversion in DS to DS with AD and new insights into AD itself resulted from our studies and will be shown.