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:
  • 金额:
    $ 36.16万
  • 依托单位:
  • 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.
7.摘要 阿尔茨海默病(Alzheimer's disease,AD)是导致痴呆的主要神经退行性疾病。原发性神经病理学 AD的病变是细胞外的纤维化β淀粉样蛋白(Aβ)斑块和细胞内的神经纤维化斑块。 过度磷酸化tau(p-tau)蛋白的缠结。成年神经发生的损伤是一个早期事件 在AD的发展中。最近的一个假说(“病原体假说”)提出,单纯疱疹病毒 1(HSV-1)在AD的发病中起相关作用。小鼠中枢神经系统中HSV-1再活化的结果 中枢神经系统(CNS)是由海马中受损的NPC神经发生引起的认知缺陷。 HSV-1感染导致Aβ42在海马的NPC中积累,这些小鼠证实了 与淀粉样β蛋白积聚有关的神经发生受损。 在本提案中,我们的目标是专门研究HSV-1再活化对人的免疫功能的影响。 NPC的神经元分化和经历病毒感染的细胞中AD分子标志的产生 重新激活我们提出以下补充目的:1)分析HSV-1再活化的影响 在神经发生方面,如NPC增殖和分化; 2)分析 联合荧光免疫分析法检测HSV-1再活化过程中NPC中Aβ肽和tau蛋白的过度磷酸化 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,在AD期间, 阿尔茨海默氏病的早期阶段,可能是基础,至少部分,认知缺陷。虽然不正常 NPC的神经发生和认知能力下降已经在HSV-1再激活的小鼠模型中描述, 目前尚不清楚这些结果是否可归因于NPC中的病毒再活化。 补充目标2与AD相关,因为从熟悉的阿尔茨海默氏症小鼠模型中分离的NPC 疾病表现出tau过度磷酸化。来自该体内模型的结果表明: 过度磷酸化是神经发生受损的主要原因; ii)Aβ水平似乎不是神经发生受损的主要原因。 NPCs神经发生改变的主要因素。然而,最近的一项研究表明, 在HSV-1小鼠模型中,NPC中的蓄积是神经发生受损的主要原因 重新激活然而,重要的是要注意,在这项研究中, NSC/NPCs尚未研究。我们建议研究Aβ水平的改变或 过度磷酸化的tau蛋白跟随HSV-1再活化,以及这些AD之一的水平增加是否是可能的。 分子标志可能出现在经历HSV-1再活化的NPC中。

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:
  • 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
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David C. Bloom其他文献

Phosphorylated-tau associates with HSV-1 chromatin and correlates with nuclear speckles decondensation in low-density host chromatin regions
磷酸化tau 与单纯疱疹病毒 1 染色质相关联,并与低密度宿主染色质区域的核斑点解凝聚相关。
  • DOI:
    10.1016/j.nbd.2025.106804
  • 发表时间:
    2025-03-01
  • 期刊:
  • 影响因子:
    5.600
  • 作者:
    Leonardo D'Aiuto;Jill K. Caldwell;Terri G. Edwards;Chaoming Zhou;Matthew L. McDonald;Roberto Di Maio;Wood A. Joel;Vanesa R. Hyde;Callen T. Wallace;Simon C. Watkins;Maribeth A. Wesesky;Or A. Shemesh;Vishwajit L. Nimgaonkar;David C. Bloom
  • 通讯作者:
    David C. Bloom
Herpes simplex virus-1 and varicella-zoster virus latency in ganglia
  • DOI:
    10.1080/13550280390194000
  • 发表时间:
    2003-03-01
  • 期刊:
  • 影响因子:
    1.900
  • 作者:
    Bradley M. Mitchell;David C. Bloom;Randall J. Cohrs;Donald H. Gilden;Peter G. E. Kennedy
  • 通讯作者:
    Peter G. E. Kennedy
801. RNA Gene Therapy Targeting Herpes Simplex Virus
  • DOI:
    10.1016/j.ymthe.2006.08.890
  • 发表时间:
    2006-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jia Liu;Sonal S. Tuli;David C. Bloom;Gregory S. Schultz;Steve C. Ghivizzani;Alfred S. Lewin
  • 通讯作者:
    Alfred S. Lewin
Posterior ankyloglossia: A case report
  • DOI:
    10.1016/j.ijporl.2009.02.011
  • 发表时间:
    2009-06-01
  • 期刊:
  • 影响因子:
  • 作者:
    Michael W. Chu;David C. Bloom
  • 通讯作者:
    David C. Bloom

David C. Bloom的其他文献

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{{ truncateString('David C. Bloom', 18)}}的其他基金

Effects of HSV-1 infection on neural progenitor cell biology in vitro and in vivo
HSV-1感染对神经祖细胞体外和体内生物学的影响
  • 批准号:
    10201788
  • 财政年份:
    2020
  • 资助金额:
    $ 36.16万
  • 项目类别:
Effects of HSV-1 infection on neural progenitor cell biology in vitro and in vivo
HSV-1感染对神经祖细胞体外和体内生物学的影响
  • 批准号:
    10623148
  • 财政年份:
    2020
  • 资助金额:
    $ 36.16万
  • 项目类别:
Effects of HSV-1 infection on neural progenitor cell biology in vitro and in vivo
HSV-1感染对神经祖细胞体外和体内生物学的影响
  • 批准号:
    10047416
  • 财政年份:
    2020
  • 资助金额:
    $ 36.16万
  • 项目类别:
Effects of HSV-1 infection on neural progenitor cell biology in vitro and in vivo
HSV-1感染对神经祖细胞体外和体内生物学的影响
  • 批准号:
    10395571
  • 财政年份:
    2020
  • 资助金额:
    $ 36.16万
  • 项目类别:
Function of histone chaperones in HSV-1 chromatin sturcture during latency, establishing maintenance and reactivation
潜伏期 HSV-1 染色质结构中组蛋白伴侣的功能、建立维持和重新激活
  • 批准号:
    8930277
  • 财政年份:
    2015
  • 资助金额:
    $ 36.16万
  • 项目类别:
Regulation of lytic and latent infection by HSV-1 encoded miRNAs
HSV-1 编码的 miRNA 对裂解和潜伏感染的调节
  • 批准号:
    8219674
  • 财政年份:
    2012
  • 资助金额:
    $ 36.16万
  • 项目类别:
Regulation of lytic and latent infection by HSV-1 encoded miRNAs
HSV-1 编码的 miRNA 对裂解和潜伏感染的调节
  • 批准号:
    8414420
  • 财政年份:
    2012
  • 资助金额:
    $ 36.16万
  • 项目类别:
Regulation of lytic and latent infection by HSV-1 encoded miRNAs
HSV-1 编码的 miRNA 对裂解和潜伏感染的调节
  • 批准号:
    8602830
  • 财政年份:
    2012
  • 资助金额:
    $ 36.16万
  • 项目类别:
Molecular Genetics of HSV Reactivation
HSV 再激活的分子遗传学
  • 批准号:
    8187898
  • 财政年份:
    2011
  • 资助金额:
    $ 36.16万
  • 项目类别:
Molecular Genetics of HSV Reactivation
HSV 再激活的分子遗传学
  • 批准号:
    8696998
  • 财政年份:
    2011
  • 资助金额:
    $ 36.16万
  • 项目类别:

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