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.
年龄是神经退化疾病的最大风险因素。但为什么有些人在衰老时认知功能没有变化、而其他人的认知功能则会下降并患阿尔茨海默氏症？在这项研究中，Bruce Yankner及同事发现，在衰老过程中，一种被称为REST (即repressor element 1-silencing transcription factor的缩写，亦称为NRSF)的蛋白在人的皮层和海马体神经元中越来越多地表达。REST水平与认知保持和长寿强相关。REST抑制促进细胞死亡和阿尔茨海默氏症病理的基因，诱导那些介导应激反应的基因。而且，REST还保护神经元不受氧化应激和β-淀粉质蛋白毒性的影响。将REST从小鼠大脑删除导致与年龄相关的神经细胞死亡。在轻度认知受损或患阿尔茨海默氏症的人类中，REST被从神经元的细胞核中排除出来，这种排除与自吞作用和误折叠的蛋白有关。这项工作表明，REST的激发状态在衰老大脑中也许能将神经保护与神经退化区分开来。