Aging, Herpesviruses, and Alzheimer's Disease

衰老、疱疹病毒和阿尔茨海默病

• 批准号: 6948253
• 负责人: JAMES M HILL
• 金额: $ 17.57万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6948253
• 关键词: Alzheimer' s disease; aging; apolipoprotein E; brain morphology; herpes simplex virus 1; morphometry; neural degeneration; neuritic plaques; neurofibrillary tangles; neuropathology; polymerase chain reaction; trigeminal neuralgia; virus DNA

DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) is latent in the trigeminal ganglia (TG) of most people. HSV-1 can also be latent in the human brain. Our hypothesis is that during the lifetime of a latently infected person, the combination of repeated neuronal reactivations of HSV-1 and the presence of a genetic factor, Apolipoprotein E (ApoE) allele e4, leads to chronic cerebral inflammation, neuronal degeneration, and an increased risk of Alzheimer's disease (AD). Our research team will test this hypothesis using autopsy specimens from a repository of 1,266 cases containing neuropathologically confirmed AD or cognitively normal patients. The Specific Aims are: Aim 1: (A) Quantitate HSV-1 DNA in AD and normal brain in 8 brain regions [entorhinal cortex, hippocampus, pons, cerebellum, and neocortex (temporal, parietal, occipital, and frontal)] that are known to exhibit varying degrees of AD lesions. The presence and genome copy numbers of HSV-1 DNA will be determined in these 8 brain regions and a newly developed Neuroinvasive Score will be used to assess the HSV-1 phenotype for each patient. Neuroinvasive Scores will range from 0 (no HSV-1 DNA in TG or any brain regions) to 9 (HSV-1 DNA in TG and all 8 brain regions). We have new evidence that HSV-1 DNA can be quantitated in specific brain regions. (B) Compare the neuropathological severity (tangles and plaques) to the Neuroinvasive Score. Since AD pathology generally exhibits bilateral symmetry, we will analyze tissue from one side of the brain by quantitative morphometric neuropathological methods and employ quantitative analytical methods to measure the HSV-1 DNA and HSV-1 RNA in the opposite hemisphere. (C) Determine the relationship between the Neuroinvasive Score and the presence of ApoE e4, relative to the occurrence of AD. Aim 2: (A) Quantify the HSV-1 latency-associated transcripts (LAT) in tissues positive for HSV-1 DNA. We have new evidence that HSV-1 LAT can be quantitated in human brain regions. (B) Detect and quantitate HSV-1 mRNAs in tissues positive for HSV-1. This project could lead to strategies to identify high-risk individuals who would be treated with antivirals, thus reducing their risk of developing AD.

描述（由申请人提供）：单纯疱疹病毒类型1（HSV-1）在大多数人的三叉神经节（TG）中是潜在的。 HSV-1在人脑中也可以潜在。我们的假设是，在一个潜在感染的人的一生中，HSV-1的重复神经元重新激活以及遗传因子的存在载脂蛋白E（APOE）等位基因E4，导致慢性脑炎症，神经元，神经元，神经元，Alzheimer's病（AD）的风险增加。我们的研究团队将使用1,266例含有神经病理学确认的AD或认知正常患者的存储库中的尸检标本来检验这一假设。具体目的是：AIM 1：（a）在8个脑区域中量化AD和正常脑中的HSV-1 DNA [内嗅皮层，海马，脑海，小脑和新皮层（颞，顶枕，枕骨和额叶）]，这些[已知在Ad varying dem varying Gresions varying Gresions]中。 HSV-1 DNA的存在和基因组拷贝数将在这8个大脑区域确定，新开发的神经侵染评分将用于评估每个患者的HSV-1表型。神经脱落得分的范围从0（TG或任何大脑区域中无HSV-1 DNA）到9（TG中的HSV-1 DNA和所有8个大脑区域）。我们有新的证据表明可以在特定的大脑区域中定量HSV-1 DNA。 （b）将神经病理严重程度（缠结和斑块）与神经侵染评分进行比较。由于AD病理通常表现出双侧对称性，因此我们将通过定量形态学神经病理学方法分析从大脑的一侧分析组织，并采用定量分析方法来测量相对半球的HSV-1 DNA和HSV-1 RNA。 （c）确定与AD的发生之间的神经侵染评分与APOE E4的存在之间的关系。 AIM 2：（a）在HSV-1 DNA呈阳性的组织中量化与HSV-1潜伏期相关的转录物（LAT）。我们有新的证据表明可以在人脑区域定量HSV-1 LAT。 （b）检测并定量HSV-1的组织中HSV-1 mRNA。该项目可能会导致策略确定将接受抗病毒药治疗的高风险个人，从而降低其发展AD的风险。