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

水痘带状疱疹病毒（VZV）潜伏在>90%的人群中，并重新激活以产生带状疱疹，如 中风（VZV血管病变）。与阿尔茨海默病（AD）类似，VZV再激活是一种 老年人;产生脑缺血/出血和神经炎症;并可长期存在 认知障碍和痴呆。此外，多项流行病学研究表明，带状疱疹 显着增加痴呆症的风险，抗病毒治疗降低风险。我们的初步研究支持 VZV加速AD的生物相容性，因为VZV感染的脊髓星形胶质细胞产生细胞内 胰淀素、Aβ42和淀粉样蛋白; VZV血管病变患者的脑脊液（CSF）中含有显著的 对应于抗VZV抗体滴度的升高的淀粉样蛋白水平;以及来自VZV-1的上清液和CSF。 感染的细胞/个体诱导淀粉样蛋白形成。VZV感染的感觉神经元的RNA测序分析 与模拟感染的细胞相比，显示AD相关途径的显著富集，包括增加 淀粉样蛋白加工、胰岛素信号传导中断、补体激活和神经元损伤。额外 初步研究显示胰淀素沿着VZV感染的感觉神经元突起和突触沉积; 这一发现是重要的，因为在AD小鼠模型中，沿着神经突沿着的淀粉样蛋白生成肽被 显示激活补体并标记神经突以修剪小胶质细胞。综合考虑，我们假设， 结合宿主和其他环境因素，VZV在老年人中的再激活加速了AD 通过促进AD中已建立的病理过程，特别是神经炎症， 淀粉样蛋白沉积和补体介导的异常突触修剪和功能障碍。为了验证这一 假设，我们将：（目的1）确定VZV感染的原代人海马神经元是否表现出类似的 如AD中所述的病理学变化，包括促炎性和淀粉样蛋白生成 （目的2）描述VZV诱导的补体激活在神经细胞中的作用。 变性/功能障碍。我们的研究是重要的，因为了解VZV如何有助于AD 发病机制将为诊断和治疗提供早期靶点（即带状疱疹疫苗接种或预防性治疗）。 抗病毒治疗），这可能会潜在地减缓或甚至停止进展为临床痴呆和死亡。

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.