REST and the regulation of stress resistance, brain aging, and Alzheimer’s disease
Citation
Drake, Derek. 2016. REST and the regulation of stress resistance, brain aging, and Alzheimer’s disease. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.Abstract
Understanding how age-related stress in the brain is managed over a lifetime to maintain neuronal and cognitive function and prevent neurodegeneration will be critical for developing therapies to promote healthy aging. Here we show that repressor element 1-silencing transcription factor (REST) is induced in neurons of cognitively-intact aged individuals, but not those with Alzheimer’s disease (AD). REST protects against factors associated with AD, such as neuronal apoptosis and AD neuropathology, through direct binding and repression of pro-apoptotic genes and genes that contribute to AD neuropathology. REST nuclear levels in prefrontal cortex pyramidal neurons also correlate with increased AD age of onset and decreased AD neuropathology. REST protects against toxic insults associated with aging, such as oxidative stress. Moreover, REST regulates FOXO1, a fundamental regulator of the response to oxidative stress, to provide oxidative stress protection. REST and FOXO1 nuclear levels correlate in aging human cortical neurons. Furthermore, REST and FOXO1 expression are correlated with the expression of FOXO1-regulated genes that protect against oxidative stress in aged prefrontal cortex. REST also downregulates miR- 132 and miR-212, microRNAs that repress FOXO1 expression, and sensitize to oxidative stress. High levels of REST in the nucleus correlate with reduced longitudinal cognitive decline during aging. Moreover, REST nuclear levels account for a significant fraction of the variability of cognitive decline in the aging human population by a mixed model analysis. These results suggest that the neuroprotective function of REST is mediated, at least in part, through regulation of FOXO1 and miR-132/miR-212, and that REST is a critical determinant of stress resistance and cognitive preservation during aging.Terms of Use
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http://nrs.harvard.edu/urn-3:HUL.InstRepos:33493396
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