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

基本信息

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
项目类别：
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

项目摘要

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.

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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