Aging, Herpesviruses, and Alzheimer's Disease

描述（由申请人提供）：1型单纯疱疹病毒（HSV-1）潜伏在大多数人的三叉神经节（TG）中。HSV-1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子载脂蛋白E（ApoE）等位基因e4的存在的组合，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1,266例神经病理学确诊的AD或认知正常患者的尸检标本来验证这一假设。具体目标是：目标1：（A）定量AD和正常脑中已知表现出不同程度AD病变的8个脑区域[内嗅皮质、海马、脑桥、小脑和新皮质（颞叶、顶叶、枕叶和额叶）]中的HSV-1 DNA。将确定这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性评分评估每例患者的HSV-1表型。神经侵入性评分范围为0（TG或任何脑区中无HSV-1 DNA）至9（TG和所有8个脑区中有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定量。(B)将神经病理学严重程度（缠结和斑块）与神经侵入性评分进行比较。由于AD病理学通常表现出双侧对称性，我们将通过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相对半球中的HSV-1 DNA和HSV-1 RNA。(C)确定神经侵袭性评分与ApoE e4存在之间的关系，相对于AD的发生。目的2：（A）定量HSV-1 DNA阳性组织中的HSV-1潜伏相关转录物（LAT）。我们有新的证据表明，HSV-1 LAT可以在人脑区域定量。(B)检测并定量HSV-1阳性组织中的HSV-1 mRNA。该项目可能会导致战略，以确定高风险的个人谁将与抗病毒药物治疗，从而降低他们的发展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.