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.

项目摘要 我们提出了一个艾滋病毒和阿尔茨海默病（AD）实验室之间的合作项目，以调查 HIV感染和淀粉样蛋白β（Aβ）（衰老和AD的关键标志）之间的潜在协同作用， 记忆受损接受抗逆转录病毒治疗的艾滋病毒感染者中有一半会出现神经认知障碍（NCI） 尽管艾滋病病毒的大脑负担很低。年龄是影响NCI进展的最一致因素。我们复制了 在感染EcoHIV（一种小鼠嗜性HIV）的常规小鼠中的HIV-NCI发病机制。项目中的MPI， 博士Arancio报道，非突触毒性剂量的外源性oAβ和Tau（另一种AD标志）协同作用， 提示AD蛋白具有致病潜力 达到亚临床浓度我们的联合初步结果表明，类似的合作发生在 向EcoHIV感染的小鼠或在培养物中或在EcoHIV感染后给予次优剂量的oAβ， 认知正常的APP/PS1小鼠，一种内源性oAβ蓄积伴AD病理的模型。我们 提出HIV和亚临床oAβ过程合作破坏突触可塑性，加剧HIV- NCI超越了每一个特工。具体目的是：1）确定增强的HIV-NCI发病机制的具体情况 在EcoHIV感染小鼠中，在显示AD病理学之前积累内源性oAβ。(A)优化起始 （B）确定疾病时HIV-NCI的严重程度 感染的oAβ表达小鼠的发病率。如果衰老的hAPP-KI小鼠，一种迟发性AD模型，在 APP/PS1将用于后续研究。2)使用目标1中的模型，我们将进行下一代 与对照相比，在达到HIV疾病状态后感染小鼠中的RNA测序（RNA-seq）： 从海马（HPC）、前额叶皮层（PFC）和纹状体（STR）生成转录组，并定义 与HIV和oAβ共同引起的记忆缺陷特别相关的生物学过程; B）证实 在HPC和STR提取物中通过RT-QPCR检测一些转录物;和C）在HPC和STR提取物中进行有限的核-RNA-seq分析， HPC将改变的HIV-oAβ过程/转录物分配给特定的细胞类型。3)研究分子机制 负责促进HIV-NCI发病机制的设置自然产生的亚临床水平的人类 小鼠中的oAβ。(A)由于HIV和Aβ都干扰了wnt信号并导致树突修剪， 骨髓细胞的感染与Aβ一起在树突完整性的Wnt功能失调中起作用。B）自EcoHIV 在小鼠中下调CaMKII和CREB研究潜在的Aβ-HIV会聚在oAβ失调中的作用。 CREB在突触强化中的作用。研究将包括EcoHIV感染的中度和迟发性AD小鼠， 学习记忆、HPC长时程增强、HPC突触树突完整性、凋亡、APP测试 处理，淀粉样蛋白病理学系统和脑HIV负荷，小鼠脑和选择细胞的生物信息学 类型，并使用控制非神经致病性EcoHIV病毒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.