Routes to enhanced HIV neuropathogenesis through expression of subclinical levels of endogenous amyloid-beta

通过表达亚临床水平的内源性β淀粉样蛋白增强HIV神经发病机制的途径

• 批准号: 10206405
• 负责人: OTTAVIO ARANCIO
• 金额: $ 86.85万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206405
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apoptosis; Bioinformatics; Biological; Biological Assay; Biological Process; Brain; Brain Diseases; Brain region; CREB1 gene; Cell Culture Techniques; Characteristics; Cognition Disorders; Cognitive; Corpus striatum structure; Defect; Development; Disease; Dose; Elements; Functional disorder; Gene Expression; Gene Proteins; Genes; Goals; HIV; HIV Infections; Hippocampus (Brain); Human; Infection; Injury; Interdisciplinary Study; Joints; Knock-in Mouse; Knowledge; Laboratories; Laboratory mice; Late Onset Alzheimer Disease; Learning; Learning Disabilities; Libraries; Long-Term Potentiation; Memory; Memory impairment; Modeling; Molecular; Mus; Myeloid Cells; Neurocognitive Deficit; Neuronal Plasticity; Neurons; Neuropathogenesis; Nuclear RNA; Onset of illness; Overlapping Genes; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Prefrontal Cortex; Presenile Alzheimer Dementia; Process; Proteins; Proteolysis; Reporting; Risk; Rodent; Role; Route; Senile Plaques; Severities; Side; Site; Slice; Specificity; Synapses; Synaptic plasticity; System; Systems Biology; Testing; Transcript; Transgenes; Transgenic Mice; Virus; WNT Signaling Pathway; Wild Type Mouse; Work; age related neurodegeneration; amyloid pathology; amyloid precursor protein processing; antiretroviral therapy; brain cell; calmodulin-dependent protein kinase II; cell type; experimental study; mouse model; mutant; neuropathology; next generation; oAβ; overexpression; pre-clinical; synergism; tau Proteins; therapy development; transcriptome; transcriptome sequencing

PROJECT SUMMARY We propose a collaborative project between HIV and Alzheimer's Disease (AD) laboratories to investigate potential synergy between HIV infection and amyloid β (Aβ), a key hallmark of aging and AD, in promoting memory impairment. Half of HIV patients on antiretroviral therapy develop neurocognitive impairments (NCI) despite low HIV brain burdens. Age is the most consistent factor affecting NCI progression. We reproduced HIV-NCI pathogenesis in conventional mice infected with EcoHIV, a mouse-tropic HIV. The MPI in the project, Dr. Arancio, reported that non-synaptotoxic doses of exogenous oAβ and Tau, another AD hallmark, cooperate in synaptic dysfunction and memory impairment in mice, suggesting that AD proteins have pathogenic potential at their subclinical concentrations. Our joint preliminary results indicate that similar cooperation occurs after administration of a suboptimal oAβ dose to EcoHIV infected mice or in culture or after EcoHIV infection of cognitively normal APP/PS1 mice, a model of endogenous oAβ accumulation followed by AD pathology. We propose that HIV and subclinical oAβ processes cooperate in disrupting synaptic plasticity to exacerbate HIV- NCI beyond each agent alone. The Specific Aims are to: 1) Define specifics of enhanced HIV-NCI pathogenesis in EcoHIV infected mice accumulating endogenous oAβ prior to showing AD pathology. (A) optimize the onset of memory deficits with EcoHIV infection in preclinical APP/PS1 mice; (B) determine HIV-NCI severity at disease onset by infected oAβ expressing mice for. If aging hAPP-KI mice, a late onset AD model, reproduce findings in APP/PS1 it will be used in subsequent studies. 2) Using a model from Aim 1, we will conduct next generation RNA sequencing (RNA-seq) in infected mice upon reaching HIV disease state compared to controls to: A) generate transcriptome from hippocampus (HPC), prefrontal cortex (PFC), and striatum (STR), and define biological processes specifically associated with memory defects caused jointly by HIV and oAβ; B) confirm some transcripts by RT-QPCR in HPC and STR extracts; and C) conduct limited nuclear-RNA-seq analysis in HPC to assign altered HIV-oAβ processes/transcripts to specific cell types. 3) Study molecular mechanisms responsible for promoting HIV-NCI pathogenesis in the setting of naturally produced subclinical levels of human oAβ in mice. (A) since both HIV and Aβ disturb wnt signaling and cause dendritic pruning, examine how HIV infection of myeloid cells works with Aβ in dysregulating Wnt function in dendritic integrity. B) since EcoHIV downmodulates CaMKII and CREB in mice study potential Aβ-HIV convergence in oAβ dysregulation of the CREB role in synaptic strengthening. Studies will include EcoHIV infection of moderate and late onset AD mice, tests of learning and memory, HPC long-term potentiation HPC synaptodendritic integrity, apoptosis, APP processing, and amyloid pathology system and brain HIV burdens, bioinformatics of mouse brain and select cell types, and use of control non-neuropathogenic EcoHIV∆ Nef.

项目总结 我们提出了一个HIV和阿尔茨海默病(AD)实验室之间的合作项目来研究 艾滋病毒感染和淀粉样蛋白β(Aβ)之间的潜在协同作用在促进 记忆力受损。接受抗逆转录病毒治疗的HIV患者中有一半会出现神经认知障碍(NCI) 尽管艾滋病毒对大脑的负担很低。年龄是影响NCI进展的最一致的因素。我们复制了 HIV-NCI的发病机制是感染EcoHIV的常规小鼠，一种亲小鼠的HIV。项目中的MPI， Arancio博士报告说，非突触毒性剂量的外源性OAβ和另一个AD标志Tau合作 在小鼠突触功能障碍和记忆障碍方面，提示AD蛋白具有致病潜力 在他们的亚临床浓度。我们的联合初步结果表明，类似的合作发生在 对EcoHIV感染的小鼠或在培养中或在EcoHIV感染后给药亚最佳的OAβ剂量 认知正常的APP/PS1小鼠，内源性OAβ蓄积继而AD病理模型。我们 认为艾滋病毒和亚临床OAβ过程在破坏突触可塑性方面协同作用，从而加剧艾滋病毒- NCI，而不是每个代理。其具体目的是：1)明确增强型HIV-NCI发病机制的具体特征 在EcoHIV感染的小鼠中，在表现出AD病理之前积累了内源性的OAβ。(一)优化启动 临床前APP/PS1小鼠感染EcoHIV后记忆缺陷的研究；(B)确定疾病时HIV-NCI的严重程度 由感染的OAβ表达的小鼠起病。如果衰老的Happ-Ki小鼠，一种迟发性AD模型，复制了 APP/PS1它将在后续研究中使用。2)使用目标1的模型，我们将进行下一代 与对照组相比，感染艾滋病毒的小鼠达到疾病状态后的RNA测序(rna-seq)：a) 从海马体(HPC)、前额叶皮质(PFC)和纹状体(STR)生成转录组，并定义 与艾滋病毒和骨质疏松症β共同引起的记忆缺陷有关的生物过程；B)确认 在HPC和STR提取液中的一些RT-QPCR转录本；以及C)在 HPC将改变的艾滋病毒-OAβ过程/转录本分配给特定类型的细胞。3)研究分子机制 负责在人类自然产生的亚临床水平下促进HIV-NCI的发病 小鼠的OAβ。(A)由于艾滋病毒和Aβ都干扰了WNT信号并导致树突修剪，研究艾滋病毒是如何 髓系细胞感染与Aβ共同作用于树突状细胞完整性中的Wnt功能失调。B)自生态艾滋病毒以来 下调CaMKII和CREB在小鼠中的表达研究Aβ与艾滋病病毒在骨性关节炎β表达异常中的融合 CREB在突触强化中的作用。研究将包括中晚期阿尔茨海默病小鼠的生态艾滋病毒感染， 学习记忆、HPC长时程增强、HPC突触树突完整性、细胞凋亡、APP测试 加工，淀粉样蛋白病理系统和脑HIV负荷，小鼠脑和选定细胞的生物信息学 类型，并使用对照非神经致病的EcoHIV∆Nef。

项目成果

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice.

• DOI: 10.1038/s41598-023-33491-7
• 发表时间: 2023-04-21
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Kim, Boe-Hyun;Hadas, Eran;Kelschenbach, Jennifer;Chao, Wei;Gu, Chao-Jiang;Potash, Mary Jane;Volsky, David J.
• 通讯作者: Volsky, David J.