REST and stress resistance in ageing and Alzheimer's disease

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 [beta]-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 [beta]-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. REST, a developmental regulator, is markedly induced in human neurons during ageing but is lost in Alzheimer's disease; REST represses genes that promote neurodegeneration, is neuroprotective in animal models, and is associated with cognitive preservation and longevity in humans. REST protein counters neurodegeneration Age is the biggest risk factor for neurodegenerative disease. But why do some age with cognitive function intact, yet others decline and develop Alzheimer's disease? Here Bruce Yankner and colleagues show that during ageing, a protein known as REST (repressor element 1-silencing transcription factor, also called NRSF) is increasingly expressed in human cortical and hippocampal neurons. REST levels are strongly correlated with cognitive preservation and longevity. REST represses genes that promote cell death and Alzheimer's disease pathology and induces those that mediate the stress response. Moreover, REST protects neurons from oxidative stress and amyloid [beta]-protein toxicity. Deleting REST from the mouse brain results in age-related neuronal cell death. And, in humans with mild cognitive impairment or Alzheimer's disease, REST is excluded from the nucleus in neurons, and this exclusion is associated with autophagy and misfolded proteins. This work suggests that the activation state of REST may distinguish neuroprotection from neurodegeneration in the ageing brain.
Author(s): Tao Lu [sup.1] , Liviu Aron [sup.1] , Joseph Zullo [sup.1] , Ying Pan [sup.1] , Haeyoung Kim [sup.1] , Yiwen Chen [sup.2] , Tun-Hsiang Yang [sup.1] , Hyun-Min [...]