DNA Damage and Neurodegeneration in the Aging Brain

描述（申请人提供）：大脑老化是老年人认知能力下降的原因之一，也是神经退行性疾病的主要危险因素。最近一项令人兴奋的进展是阐明了衰老的人类大脑中DMA损伤的模式，该模式与介导突触可塑性、囊泡运输和线粒体功能的基因表达减少有关。我们发现的大脑衰老的“遗传特征”可以解释，至少部分，通过氧化DNA损伤脆弱的基因启动子，为理解大脑如何衰老提供了一个新的概念框架。此外，通过获得包含长寿基因Sirtl、转录共抑制因子NCOR1和DNA修复酶hOGG1的核蛋白复合物参与的证据，我们已经开始确定受损基因沉默的机制。我们的初步研究也提出了与年龄有关的可能性。DNA损伤和基因沉默可能导致阿尔茨海默病的发病。Cdk5失调的Ck-p25转基因小鼠模型的发展进一步支持了这一假设，该模型显示出明显增加的DNA损伤和阿尔茨海默病的病理特征。这些发现为我们的假设提供了基础，即DNA损伤有助于减少老化大脑中重要神经元基因的表达，这一过程可能是认知能力下降和神经变性易感性的基础。本课题的研究将建立正常衰老人类大脑中基因表达和DNA损伤的全基因组数据库，并将研究新定义的涉及长寿基因sirt1的DNA损伤沉默复合体的作用。将产生过表达DNA修复酶的转基因小鼠，并与：APPsw和Ck-p25转基因小鼠模型配对，以确定年龄相关DNA损伤在衰老认知能力下降和阿尔茨海默病病理中的作用。此外，自噬受损在衰老大脑中氧化DNA损伤和蛋白质聚集机制中的作用将被研究。最后，将在正常衰老小鼠和人类神经退行性疾病小鼠模型中测试一组具有潜在治疗作用的sirtl激活化合物。这些研究可能为大脑衰老提供新的见解，具有潜在的重要治疗意义。

DESCRIPTION (provided by applicant): The aging of the brain is a cause of cognitive decline in the elderly and the major risk factor for neurodegenerative diseases. An exciting recent development is the elucidation of a pattern of DMA damage in the aging human brain that is associated with reduced expression of genes that mediate synaptic plasticity, vesicular transport and mitochondrial function. Our finding of a "genetic signature" of brain aging that can be explained, at least in part, by oxidative DNA damage to vulnerable gene promoters provides a novel conceptual framework for understanding how the brain ages. Furthermore, we have begun to define the mechanism by which damaged genes are silenced by obtaining evidence for the involvement of a nuclear protein complex that contains the longevity gene Sirtl, the transcriptional co-repressor NCOR1, and the DNA repair enzyme hOGG1. Our preliminary studies also raise the possibility that age-related .DNA damage and gene silencing may predispose to the pathology of Alzheimer's disease. This hypothesis is further supported by the development of the Ck-p25 transgenic mouse model of Cdk5 dysregulation that shows markedly increased DNA damage and features of the pathology of Alzheimer's disease. These findings provide the basis for our hypothesis that DNA damage contributes to reduced expression of important neuronal genes in the aging brain, and that this process may underlie cognitive decline and vulnerability to neurodegeneration. The studies in this proposal will establish a genome-wide database of gene expression and DNA damage in the normal aging human brain, and will investigate the role of a newly defined DNA damage silencing complex involving the longevity gene Sirt 1. Transgenic mice that overexpress DNA repair enzymes will be generated and mated with: APPsw and Ck-p25 transgenic mouse models to determine the role of age-related DNA damage in the cognitive decline of aging and the pathology of Alzheimer's disease. Moreover, the role of impaired autophagy as a mechanism of oxidative DNA damage and protein aggregation in the aging brain will be investigated. Finally, a novel set of potentially therapeutic Sirtl-activating compounds will be tested in normal aging mice and in mouse models of human neurodegenerative diseases. These studies may provide new insights into brain aging, with potentially significant therapeutic implications.