Effects of HSV-1 reactivation from latency on aspects of neural precursor cells neurogenesis and accumulation of Alzheimer's molecular hallmarks

HSV-1从潜伏期重新激活对神经前体细胞神经发生和阿尔茨海默病分子标志积累的影响

• 批准号: 10710940
• 负责人: David C. Bloom
• 金额: $ 36.16万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710940
• 关键词: 3-Dimensional; Acceleration; Address; Affect; Alzheimer' s Disease; Amyloid beta-42; Amyloid beta-Protein; Attenuated; Autopsy; Biology; Brain; Cell Culture Techniques; Cell Death; Cell Differentiation process; Cell Separation; Cells; Central Nervous System; Clinical; Cognition; DNA; Data; Defect; Dementia; Development; Disease; Event; Exhibits; Fluorescent in Situ Hybridization; Functional disorder; Generations; Health; Herpes Simplex Infections; Herpesvirus 1; Hippocampus; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Infection; Lesion; Link; Modeling; Molecular; Molecular Disease; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuronal Differentiation; Neurons; Outcome; Pathogenesis; Pathology; Peptides; Phase; Play; Positron-Emission Tomography; Prevention therapy; Production; Proliferating; Prophylactic treatment; Proteins; RNA; Reporting; Risk Factors; Role; Senile Plaques; Site; Symptoms; Synapses; Transgenic Mice; Tropism; Viral; Virus; abeta accumulation; adult neurogenesis; aging population; amyloid peptide; brain tissue; experimental study; extracellular; familial Alzheimer disease; human model; hyperphosphorylated tau; imaging study; in vivo; in vivo Model; induced pluripotent stem cell; innovation; migration; mouse model; mutant; nerve stem cell; neural; neurogenesis; neuroinflammation; neuropathology; new therapeutic target; pathogen; pathogenic virus; pre-clinical; reactivation from latency; stem cell proliferation; tau Proteins; tau-1

7. ABSTRACT Alzheimer's disease (AD) is the leading neurodegenerative cause of dementia. Primary neuropathological lesions of AD are extracellular plaques of fibrillized β-amyloid (Aβ) peptides and intracellular neurofibrillary tangles of hyper-phosphorylated tau (p-tau) protein. The impairment of adult neurogenesis is an early event in the development of AD. A recent hypothesis (“pathogen hypothesis”) proposes that herpes simplex virus 1 (HSV-1) plays a relevant role in the onset of AD. A consequence of HSV-1 reactivation in murine central nervous system (CNS) is cognition deficits caused by impaired NPCs neurogenesis in the hippocampus. HSV-1 infection results in Aβ42 accumulation in the NPCs in the hippocampus and these mice demonstrate impaired neurogenesis linked to amyloid-β protein accumulation. In the present proposal, we aim to specifically investigate the consequences of HSV-1 reactivation on neuronal differentiation of NPCs and the generation of AD molecular hallmarks in cells undergoing viral reactivation. We propose the following Supplemental Aims: 1) Analysis of the effects of HSV-1 reactivation on aspects of neurogenesis, such as NPCs proliferation and differentiation; 2) Analysis of accumulation of Aβ peptides and hyperphosphorylation of tau in NPCs during HSV-1 reactivation by combined Fluorescent in Situ Hybridization and Immunohistochemistry (FISH-IHC). Supplemental Aim 1 is relevant to AD because in vivo studies suggest that neurogenesis is impaired during early stages of Alzheimer's disease and may underlie, at least in part, cognition deficit. Although abnormal NPCs neurogenesis and cognitive decline have been described in a mouse model of HSV-1 reactivation, it is not known whether these outcomes can be attributed to viral reactivation in NPCs. Supplemental Aim 2 is relevant to AD because NPCs isolated from a murine model of familiar Alzheimer’s disease exhibit hyperphosphorylation of tau. The results from this in vivo model indicate that: i) tau hyperphosphorylation is the main contributor to impaired neurogenesis; ii) Aβ levels do not seem to be the primary factor in the alteration of NPCs neurogenesis. However, a recent study indicates that Aβ accumulation in NPCs is the major contributor to impaired neurogenesis in a murine model of HSV-1 reactivation. Nevertheless, it is important to note that in this study the tau hyperphosphorylation in NSCs/NPCs had not been investigated. We propose to investigate whether altered levels of Aβ or hyperphosphorylated tau follows HSV-1 reactivation and whether the increased levels of one of these AD molecular hallmarks may occur in NPCs undergoing to HSV-1 reactivation.

7. 摘要 阿尔茨海默氏病 (AD) 是导致痴呆症的主要原因。原发性神经病理学 AD 的病变是纤维化 β-淀粉样蛋白 (Aβ) 肽的细胞外斑块和细胞内神经原纤维 过度磷酸化 tau (p-tau) 蛋白缠结。成人神经发生受损是一个早期事件 在 AD 的发展过程中。最近的一项假说（“病原体假说”）提出，单纯疱疹病毒 1 (HSV-1) 在 AD 的发病中发挥着相关作用。小鼠中枢 HSV-1 重新激活的结果 神经系统 (CNS) 是由海马区 NPC 神经发生受损引起的认知缺陷。 HSV-1 感染导致海马 NPC 中 Aβ42 积聚，这些小鼠证明 神经发生受损与淀粉样β蛋白积累有关。 在本提案中，我们的目标是专门研究 HSV-1 重新激活对 NPC 的神经元分化以及病毒感染细胞中 AD 分子标志的产生 重新激活。我们提出以下补充目标： 1) 分析 HSV-1 重新激活的影响 神经发生方面，例如 NPC 增殖和分化； 2）积累分析 联合荧光检测 HSV-1 重新激活期间 NPC 中的 Aβ 肽和 tau 过度磷酸化 原位杂交和免疫组织化学 (FISH-IHC)。 补充目标 1 与 AD 相关，因为体内研究表明神经发生在 AD 过程中受到损害。 阿尔茨海默病的早期阶段，可能是（至少部分）认知缺陷的根源。虽然不正常 在 HSV-1 重新激活的小鼠模型中描述了 NPC 的神经发生和认知能力下降， 目前尚不清楚这些结果是否可归因于 NPC 中的病毒重新激活。 补充目标 2 与 AD 相关，因为从常见的阿尔茨海默病小鼠模型中分离出 NPC 疾病表现出 tau 蛋白过度磷酸化。该体内模型的结果表明： i) tau 过度磷酸化是神经发生受损的主要原因； ii) Aβ 水平似乎不是 NPC 神经发生改变的主要因素。然而，最近的一项研究表明，Aβ NPC 中的积累是 HSV-1 小鼠模型中神经发生受损的主要原因 重新激活。然而，值得注意的是，在这项研究中，tau 蛋白过度磷酸化 尚未对 NSC/NPC 进行调查。我们建议调查 Aβ 或 HSV-1 重新激活后过度磷酸化的 tau 蛋白以及这些 AD 之一的水平是否增加 分子标志可能出现在经历 HSV-1 重新激活的 NPC 中。

项目成果

Insights into bioinformatic approaches for repurposing compounds as anti-viral drugs.

• DOI: 10.1177/20402066211036822
• 发表时间: 2021-01
• 期刊: Antiviral chemistry & chemotherapy
• 作者: Zheng W;D'Aiuto L;Demers MJ;Muralidaran V;Wood JA;Wesesky M;Chattopadhyay A;Nimgaonkar VL
• 通讯作者: Nimgaonkar VL