DNA Damage and Neurodegeneration in the Aging Brain

描述（由申请人提供）：大脑老化是老年人认知能力下降的原因，也是神经退行性疾病的主要风险因素。一个令人兴奋的最新进展是阐明了衰老人脑中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。我们发现大脑衰老的“基因特征”可以解释，至少部分可以解释为对脆弱基因启动子的氧化DNA损伤，这为理解大脑如何衰老提供了一个新的概念框架。此外，我们已经开始定义受损基因沉默的机制，通过获得证据证明参与核蛋白复合物，其中包含长寿基因Sirt 1，转录辅阻遏物NCOR 1和DNA修复酶hOGG 1。我们的初步研究还提出了与年龄相关的DNA损伤和基因沉默可能导致阿尔茨海默病的病理学的可能性。Cdk 5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，该模型显示出显著增加的DNA损伤和阿尔茨海默病的病理学特征。这些发现为我们的假设提供了基础，即DNA损伤有助于衰老大脑中重要神经元基因表达的减少，并且这一过程可能是认知能力下降和神经退行性变脆弱性的基础。该提案中的研究将建立一个正常衰老人脑中基因表达和DNA损伤的全基因组数据库，并将研究一种新定义的涉及长寿基因Sirt 1的DNA损伤沉默复合物的作用。将产生过表达DNA修复酶的转基因小鼠，并与APPsw和Ck-p25转基因小鼠模型交配，以确定年龄相关的DNA损伤在衰老的认知能力下降和阿尔茨海默病病理学中的作用。此外，受损的自噬作为衰老大脑中氧化DNA损伤和蛋白质聚集的机制的作用将被研究。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新的潜在治疗性Sirt 1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.