The role of VZV infection in hippocampal neurons to Alzheimer's disease pathogenesis

水痘带状疱疹病毒(VZV)在90%的人群中潜伏，并重新激活以产生带状疱疹，如 以及中风(VZV血管病变)。与阿尔茨海默病(AD)类似，VZV重新激活是一种 老年人；产生脑缺血/出血和神经炎症；并可表现为长期 认知障碍和痴呆症。此外，多项流行病学研究表明，带状疱疹 显著增加了痴呆症的风险，而抗病毒治疗降低了风险。我们的初步研究支持 VZV加速AD的生物学可行性，因为VZV感染的脊髓星形胶质细胞产生细胞内 VZV血管病患者脑脊液中含有淀粉、Aβ42和淀粉样蛋白 与抗VZV抗体滴度相对应的淀粉样蛋白水平升高；VZV- 被感染的细胞/个体诱导淀粉样蛋白的形成。VZV感染感觉神经元的RNA测序分析 与模拟感染细胞相比，AD相关途径显著丰富，包括增加 淀粉样蛋白处理、胰岛素信号转导中断、补体激活和神经元损伤。其他内容 初步研究表明，胰淀素沿VZV感染的感觉神经元突起和突触沉积； 这一发现意义重大，因为在AD小鼠模型中，沿轴突的淀粉样多肽 显示激活、补充和标记神经突起以进行小胶质细胞修剪。综合来看，我们假设， 与宿主和其他环境因素相结合，VZV在老年人中的重新激活会加速AD 通过促进阿尔茨海默病已建立的病理过程，特别是神经炎症， 淀粉样蛋白沉积，以及补体介导的突触异常修剪和功能障碍。为了测试这一点 假设，我们将：(目标1)确定VZV感染的原代人类海马神经元是否表现出类似的 阿尔茨海默病的病理改变，包括促炎性和淀粉样变性的产生 以及(目的2)表征VZV诱导的补体激活在神经元中的作用 退化/功能障碍。我们的研究具有重要意义，因为了解VZV是如何导致AD的 发病机制将为诊断和治疗提供早期目标(即接种带状疱疹疫苗或预防 抗病毒治疗)，这可能会减缓甚至阻止临床痴呆和死亡的进展。

Varicella zoster virus (VZV) is latent in >90% of the population and reactivates to produce herpes zoster, as well as stroke (VZV vasculopathy). Similar to Alzheimer’s disease (AD), VZV reactivation is a disease of the elderly; produces cerebral ischemia/hemorrhage and neuroinflammation; and can present as long-term cognitive impairment and dementia. Furthermore, multiple epidemiological studies show that zoster significantly increases dementia risk and that antiviral therapy reduces risk. Our preliminary studies support the biological plausibility of VZV accelerating AD because VZV-infected spinal astrocytes produce intracellular amylin, Aβ42, and amyloid; cerebrospinal fluid (CSF) from VZV vasculopathy patients contain significantly elevated amyloid levels that correspond to anti-VZV antibody titers; and supernatant and CSF from VZV- infected cells/individuals induce amyloid formation. RNA sequencing analysis of VZV-infected sensory neurons show significant enrichment of AD-associated pathways compared to mock-infected cells, including increased amyloid processing, disruption of insulin signaling, complement activation and neuronal injury. Additional preliminary studies show deposition of amylin along VZV-infected sensory neuron processes and synapses; this finding is significant because in AD mouse models, amyloidogenic peptides along neurites have been shown to activate complement and tag the neurite for microglial pruning. Taken together, we hypothesize that, in conjunction with host and other environmental factors, VZV reactivation in the elderly accelerates AD progression by contributing to established pathological processes in AD, specifically neuroinflammation, amyloid deposition, and complement-mediated aberrant synaptic pruning and dysfunction. To test this hypothesis, we will: (Aim 1) Determine if VZV-infected primary human hippocampal neurons exhibit similar pathological changes as those described in AD, including production of a proinflammatory and amyloidogenic environment; and (Aim 2) characterize the role of VZV-induced complement activation in neuronal degeneration/dysfunction. Our studies are significant because understanding how VZV contributes to AD pathogenesis will provide early targets for diagnosis and treatment (i.e. zoster vaccination or prophylactic antiviral therapy) that may potentially slow or even halt progression to clinical dementia and death.