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.
Monday, May 26, 2014
Stress can protect from Alzheimer's disease
Yanker and his collaborators have found that levels of a neuro-protective protein called REST (repressor element 1-silencing transcription factor) are increased in the brain by any form of cellular stress (oxidative, immune, etc.) It acts by repressing genes involved in cell death and Alzheimer's dementia. REST levels in prefrontal cortical neurons are positively correlated with a measure of global cognition, and also separate measures of episodic, semantic and working memory. Measurements of autopsied brains of elderly people who have died of Alzheimer's are three times lower than in the brains of people the same age without dementia. Here is their abstract: