HSV-1 and beta-amyloid deposition

阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病， 导致记忆丧失和痴呆的功能。它影响了数百万美国人， 发病率和死亡率。AD的特征是含有淀粉样蛋白-β的神经炎性物质的积累， 斑块和细胞内tau蛋白缠结。越来越多的证据表明 单纯疱疹病毒1型（HSV-1）感染和AD。值得注意的是，在AD淀粉样蛋白中可检测到HSV-1 DNA， 斑块在人类大脑中，抗病毒阿昔洛韦据报道，以阻止积累的AD- 相关蛋白β-淀粉样蛋白。独立阿尔茨海默病的多尺度转录组分析 美国的队列研究表明，AD的病理特征与神经毒力因子密切相关， γ 134.5由HSV-1编码。然而，HSV-1在功能上参与的方式仍然存在， 大部分未知。我们最近发现γ 134.5募集并激活蛋白激酶C δ， 丝氨酸/苏氨酸激酶，其上调β-分泌酶并促进AD病理。由于病毒γ 134.5也 在自噬途径中靶向Beclin1，我们假设HSV-1介导的病毒活性可能 通过γ 134.5改变淀粉样前体蛋白及其代谢产物的稳态， AD的发展。因此，我们将研究病毒对淀粉样蛋白-β生成的调控， 阿尔茨海默病的细胞培养模型。将构建重组HSV以询问 β-分泌酶的表达。此外，我们将研究淀粉样蛋白-β清除率。基因研究将 以评估病毒对自噬机制的干扰。拟议的研究将 系统探讨与HSV-1感染相关AD的病理特征。如果成功，它将通知 为AD设计新的治疗方法。

Alzheimer's disease (AD) is a neurodegenerative disorder with progressive decline in cognitive functions leading to memory loss and dementia. It affects millions of Americans and causes significant morbidity and mortality. AD is characterized by the accumulation of amyloid-β-containing neuritic plaques and intracellular tau protein tangles in the brain. Growing evidence pinpoints a link between herpes simplex virus 1 (HSV-1) infection and AD. Notably, HSV-1 DNA is detectable in AD amyloid plaques in human brains, and antiviral acyclovir is reported to block the accumulation of the AD- associated proteins beta-amyloid. Multiscale transcriptome analysis of independent Alzheimer's cohorts in the USA suggests that AD pathology traits are closely coupled with neurovirulence factor γ134.5 encoded by HSV-1. However, the way through which HSV-1 is functionally involved remains largely unknown. We recently found that γ134.5 recruits and activates protein kinase Cδ, a host serine/threonine kinase that upregulates β-secretase and facilitates AD pathology. As viral γ134.5 also targets Beclin1 in the autophagy pathway, we hypothesize that viral activities mediated by HSV-1 may alter homeostasis of amyloid precursor protein and its metabolites through γ134.5 and facilitates the development of AD. As such, we will study viral regulation of amyloid-β generation a 3D human neural cell culture model of Alzheimer's disease. Recombinant HSV will be constructed to interrogate the expression of β-secretase. Furthermore, we will investigate amyloid-β clearance. Genetic studies will be carried out to assess viral interference of autophagy machineries. The proposed research will systematically explore pathological features of AD linked to HSV-1 infection. If successful, it will inform design of new therapeutic approach for AD.