Person:

Drake, Derek

Human neurons are functional over an entire lifetime, yet the mechanisms that preserve function and protect against neurodegeneration during ageing are unknown. Here we show that induction of the repressor element 1-silencing transcription factor (REST; also known as neuron-restrictive silencer factor, NRSF) is a universal feature of normal ageing in human cortical and hippocampal neurons. REST is lost, however, in mild cognitive impairment and Alzheimer’s disease. Chromatin immunoprecipitation with deep sequencing and expression analysis show that REST represses genes that promote cell death and Alzheimer’s disease pathology, and induces the expression of stress response genes. Moreover, REST potently protects neurons from oxidative stress and amyloid β-protein toxicity, and conditional deletion of REST in the mouse brain leads to age-related neurodegeneration. A functional orthologue of REST, Caenorhabditis elegans SPR-4, also protects against oxidative stress and amyloid β-protein toxicity. During normal ageing, REST is induced in part by cell non-autonomous Wnt signalling. However, in Alzheimer’s disease, frontotemporal dementia and dementia with Lewy bodies, REST is lost from the nucleus and appears in autophagosomes together with pathological misfolded proteins. Finally, REST levels during ageing are closely correlated with cognitive preservation and longevity. Thus, the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.

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.