Preventing Alzheimer's Disease Like Brain Pathology in HIV Infection by Targeting CCR5

通过靶向 CCR5 预防阿尔茨海默病,例如 HIV 感染中的脑病理学

基本信息

项目摘要

ABSTRACT Studies of brain tissues from people living with HIV (PLWH), as well as HIV/AIDS animal models, showed increased amyloid-β (Aβ) production and aggregation, amyloid plaques, increased Tau hyperphosphorylation (pTau) and formation of neurofibrillary tangles-like structures. Importantly, the presence of these Alzheimer’s Disease (AD)-like pathologies in PLWH is associated with increased neurodegeneration and HIV-associated neurocognitive impairment (HAND). The mechanisms through which HIV increase Aβ production, pTau pathologies, and induce AD-like central nervous system (CNS) impairment are not known. Although most PLWH who showed increased CNS amyloid plaques and pTau associated with HAND had been on long-term antiretroviral therapy (ART), the role of ART in Aβ and pTau production, and AD-like pathologies has not been investigated. Our in-vivo and ex-vivo studies demonstrated that HIV-1 infection significantly increased CNS levels of Aβ42 (the major neurotoxic component of Aβ) and pTau, and this was associated with neuronal damage and blood-brain barrier (BBB) injury. Significantly, we demonstrated that the CCR5 antagonist, maraviroc (MVC), abrogated HIV-induced production of Aβ42 and pTau, prevented HIV-induced damage to neurons and the BBB, and decreased CNS viral loads. Therefore, we hypothesize that CCR5 plays a major role in the formation of amyloid plaques and pTau pathology in PLWH and that targeting CCR5 prevents HIV-induced Aβ production, prevents the formation of amyloid plaques and pTau, and abrogates neuronal loss, and HAND. In these exploratory studies, we will use a validated HIV/AIDS animal model to test this hypothesis and further investigate the effects of a commonly prescribed antiretroviral (ARV) drug (azidothymidine [AZT]) on HIV- 1-induced amyloidogenesis, pTau and CNS injury (Aim-1), neuroinflammation and Aβ clearance (Aim-2), the metabolism of amyloid precursor proteins (APP) and Tau (Aim-3). These mechanistic studies will help determine whether HIV induce Aβ production by interfering with i) Aβ degradation and clearance, ii) APP α-secretase or β- secretase pathways; iii) the effectors and pathways associated with HIV-induce pTau, iv) the role of ARV (AZT), and v) whether CCR5 modulates these effects. Studies in this R21 application are very significant and address the NIH high priority research areas that focus on “Examining the pathophysiologic mechanisms of HIV-induced CNS dysfunction in the setting of ART…. and development of novel therapeutic approaches to mitigate CNS complications of HIV infection.” The CCR5 antagonist MVC is an FDA-approved drug and our study will determine whether MVC prevents CNS Aβ production, formation of amyloid plaques and pTau in the setting of HIV-infection and ART, and the associated mechanisms. The results will demonstrate the role of CCR5 in HIV- induced production of Aβ and pTau in the CNS and provide new approaches for therapeutically targeting CCR5 to prevent HIV-1-induced amyloidogenesis, pTau pathology, neuronal injury, and neurocognitive impairments.
摘要

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)
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CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice.
CCR5拮抗剂减少了HIV感染的HU-PBL-NSG小鼠中HIV诱导的淀粉样生成,TAU病理学,神经变性和血脑屏障的改变。
  • DOI:
    10.1186/s13024-021-00500-0
  • 发表时间:
    2021-11-22
  • 期刊:
  • 影响因子:
    15.1
  • 作者:
    Bhargavan B;Woollard SM;McMillan JE;Kanmogne GD
  • 通讯作者:
    Kanmogne GD
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GEORGETTE D. KANMOGNE其他文献

GEORGETTE D. KANMOGNE的其他文献

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{{ truncateString('GEORGETTE D. KANMOGNE', 18)}}的其他基金

PREVENTING ALZHEIMER’S DISEASE-LIKE BRAIN PATHOLOGY IN HIV INFECTION BY TARGETING CCR5
通过靶向 CCR5 预防 HIV 感染中的阿尔茨海默病样脑部病变
  • 批准号:
    10700624
  • 财政年份:
    2023
  • 资助金额:
    $ 22.98万
  • 项目类别:
Preventing Alzheimer's Disease Like Brain Pathology in HIV Infection by Targeting CCR5
通过靶向 CCR5 预防阿尔茨海默氏病,例如 HIV 感染中的脑病理学
  • 批准号:
    10161318
  • 财政年份:
    2020
  • 资助金额:
    $ 22.98万
  • 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
  • 批准号:
    8426089
  • 财政年份:
    2012
  • 资助金额:
    $ 22.98万
  • 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
  • 批准号:
    8599489
  • 财政年份:
    2012
  • 资助金额:
    $ 22.98万
  • 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
  • 批准号:
    8779742
  • 财政年份:
    2012
  • 资助金额:
    $ 22.98万
  • 项目类别:
HIV Genetic Diversity and Viral Neuropathogenesis
HIV遗传多样性和病毒神经发病机制
  • 批准号:
    8257050
  • 财政年份:
    2012
  • 资助金额:
    $ 22.98万
  • 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
  • 批准号:
    8055998
  • 财政年份:
    2008
  • 资助金额:
    $ 22.98万
  • 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
  • 批准号:
    7806523
  • 财政年份:
    2008
  • 资助金额:
    $ 22.98万
  • 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
  • 批准号:
    7619271
  • 财政年份:
    2008
  • 资助金额:
    $ 22.98万
  • 项目类别:
Blood brain barrier immune compromise in NeuroAIDS
NeuroAIDS 中的血脑屏障免疫受损
  • 批准号:
    8247819
  • 财政年份:
    2008
  • 资助金额:
    $ 22.98万
  • 项目类别:
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