Aging, Herpesviruses, and Alzheimer's Disease

描述(申请人提供)：单纯疱疹病毒1型(HSV-1)在大多数人的三叉神经节(TG)中潜伏。HSV-1病毒也可能在人脑中潜伏。我们的假设是，在潜伏感染的人的一生中，HSV-1反复的神经元重新激活和遗传因素载脂蛋白E(ApoE)等位基因e4的存在相结合，会导致慢性脑炎、神经元退化和阿尔茨海默病(AD)风险的增加。我们的研究团队将使用1266例病例的尸检样本来检验这一假设，这些病例中包含经神经病理证实的AD患者或认知正常的患者。具体目标是：目的1：(A)定量检测阿尔茨海默病患者和正常脑组织中8个已知程度不同的阿尔茨海默病患者脑区[内嗅皮层、海马体、脑桥、小脑和新皮质(颞叶、顶叶、枕叶和额叶)]的HSV-1 DNA。将在这8个脑区确定HSV-1 DNA的存在和基因组拷贝数，并将使用新开发的神经侵袭评分来评估每个患者的HSV-1表型。神经侵袭性评分将从0(TG或任何脑区没有HSV-1DNA)到9(TG和所有8个脑区都没有HSV-1DNA)。我们有新的证据表明，HSV-1 DNA可以在特定的大脑区域进行定量。(B)将神经病理严重程度(缠结和斑块)与神经侵袭评分进行比较。由于AD病理一般表现为双侧对称性，我们将采用定量形态神经病理学方法对一侧大脑组织进行分析，并采用定量分析方法检测对侧大脑半球的HSV-1DNA和HSV-1RNA。(C)确定神经侵袭评分与载脂蛋白E e4的存在之间的关系，与AD的发生有关。目的：(A)定量检测HSV-1 DNA阳性组织中的HSV-1潜伏期相关转录本(LAT)。我们有新的证据表明，HSV-1 LAT可以在人脑区域进行定量。(B)检测和定量检测HSV-1阳性组织中的HSV-1mRNAs。该项目可能导致制定战略，以确定将接受抗病毒药物治疗的高危人群，从而降低他们患AD的风险。

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.