Aging, Herpesviruses, and Alzheimer's Disease

描述（由申请人提供）：单纯疱疹病毒1型（HSV-1）潜伏在大多数人的三叉神经节（TG）中。1型单纯疱疹病毒也可以潜伏在人脑中。我们的假设是，在潜伏感染者的一生中，HSV-1的反复神经元再激活和遗传因素载脂蛋白E （ApoE）等位基因e4的存在相结合，导致慢性脑炎症、神经元变性和阿尔茨海默病（AD）的风险增加。我们的研究小组将使用来自1266例神经病理学证实的AD患者或认知正常患者的尸检标本来验证这一假设。目的1:(A)定量测定阿尔茨海默病和正常大脑中8个已知表现出不同程度阿尔茨海默病病变的脑区[内嗅皮层、海马、脑桥、小脑和新皮层（颞、顶叶、枕叶和额叶）]中HSV-1的DNA。将测定这8个脑区中HSV-1 DNA的存在和基因组拷贝数，并使用新开发的神经侵入评分（Neuroinvasive Score）来评估每位患者的HSV-1表型。神经侵入性评分范围从0 （TG或任何脑区无HSV-1 DNA）到9 （TG和所有8个脑区均有HSV-1 DNA）。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分析。(B)将神经病理严重程度（缠结和斑块）与神经侵袭性评分进行比较。由于AD病理通常表现为双侧对称性，我们将采用定量形态学神经病理学方法分析一侧大脑的组织，并采用定量分析方法测量对侧半球的HSV-1 DNA和HSV-1 RNA。(C)确定相对于AD的发生，ApoE e4的存在与Neuroinvasive Score之间的关系。目的2:(A)量化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可以在人类大脑区域进行量化。(B)在HSV-1阳性组织中检测并定量HSV-1 mrna。这个项目可能会导致识别高危人群的策略，他们将接受抗病毒治疗，从而降低他们患阿尔茨海默病的风险。

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.