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: 10415699
• 负责人: OTTAVIO ARANCIO
• 金额: $ 247.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10415699
• 关键词: Acceleration; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Apoptosis; Applications Grants; Behavioral; Biochemical; Bioinformatics; Biological; Biological Assay; Biological Process; Brain; Brain Diseases; Brain region; CREB1 gene; Ca(2+)-Calmodulin Dependent Protein Kinase; Cell Culture Techniques; Cognition Disorders; Corpus striatum structure; Defect; Development; Disease; Disease Progression; Dose; Elements; Functional disorder; Gene Expression; Genes; Goals; Grant; HIV; HIV Infections; Hippocampus (Brain); Human; Immunohistochemistry; Impaired cognition; Infection; Injury; Interdisciplinary Study; Joints; Knock-in Mouse; Knowledge; Laboratories; Late Onset Alzheimer Disease; Learning; Learning Disabilities; Libraries; Long-Term Potentiation; Memory; Memory Loss; Memory impairment; Modeling; Molecular; Mouse Strains; Mus; Mutation; Myeloid Cells; Neurocognitive Deficit; Neuronal Plasticity; Neurons; Neuropathogenesis; Nuclear RNA; Onset of illness; Overlapping Genes; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Persons; Prefrontal Cortex; Process; Proteins; Proteolysis; Reporting; Research; Research Project Grants; Role; Route; Senile Plaques; Severities; Siblings; Side; Site; Slice; Symptoms; Synapses; Synaptic plasticity; System; Systems Biology; Testing; Transcript; Transgenic Organisms; Virus; Virus Replication; WNT Signaling Pathway; Western Blotting; Work; abeta accumulation; age related; age related neurodegeneration; amyloid pathology; amyloid precursor protein processing; antiretroviral therapy; brain cell; calmodulin-dependent protein kinase II; cell type; familial Alzheimer disease; mouse model; neuropathology; next generation; novel; oAβ; pre-clinical; preference; synergism; tau Proteins; therapy development; transcriptome; transcriptome sequencing

This is a resubmission of a collaborative project between HIV and Alzheimer’s Disease (AD) laboratories to investigate potential synergy between HIV infection and amyloid β (Aβ), a hallmark of 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 Project MPI, Dr. Arancio, reported that non-synaptotoxic doses of exogenous oligomeric Aβ (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 revised preliminary results show such cooperation between EcoHIV and oAβ in multiple formats including after EcoHIV infection of AD mouse models prior to their cognitive decline. The models included transgenic APP/PS1 mouse model of familial AD (FAD) and two late onset AD (LOAD) mouse models expressing humanized AD proteins. 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) Characterize enhanced HIV-NCI pathogenesis in FAD and LOAD mouse models prior to onset of their AD symptoms. (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 APP/PS1 mice by hippocampal LTP, synaptodendritic injury, apoptosis, APP processing, and amyloid pathology (C) Conduct similar studies by EcoHIV infection of LOAD model mice expressing various humanized AD genes and select one LOAD model for further studies 2) Using APP/PS1 mice and one LOAD strain, conduct next generation RNA sequencing (RNA-seq) in EcoHIV infected mice upon reaching HIV disease state (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 gene modulation by RT-QPCR in HPC and STR extracts or by immunostaining in brain section; 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.

这是艾滋病毒和阿尔茨海默氏病（AD）实验室之间的合作项目的重新提交 研究HIV感染和淀粉样β（Aβ）的潜在协同作用，AD的标志是促进记忆 损害。抗逆转录病毒疗法的HIV患者中有一半发展神经认知障碍（NCI）dospite低 HIV脑燃烧。年龄是影响NCI进展的最一致因素。我们复制了HIV-NCI 感染EcoHIV的传统小鼠的发病机理，一种小鼠 - 热带HIV。 MPI项目Arancio博士， 报道了非鼻毒性剂量的外源性寡聚Aβ（OAβ）和Tau，另一个AD标志， 在小鼠的突触功能障碍和记忆力障碍方面合作，表明AD蛋白具有致病性 潜在的亚临床浓度。我们修订的初步结果表明 Ecohiv和OAβ的多种格式，包括AD小鼠模型的Ecohiv感染之后 衰退。这些模型包括转基因应用/ps1鼠标family AD（FAD）和两个晚期发作广告 （负载）表达人源化AD蛋白的小鼠模型。我们提出HIV和亚临床OAβ过程 合作，破坏突触可塑性，使HIV-NCI仅超过每个药物。具体目标 为：1）在FAD和负载小鼠模型中表征增强的HIV-NCI发病机理 广告符号。 （a）优化临床前应用/PS1小鼠中生态感染的内存开始； （b） 通过海马LTP，突触drimention，SynaptoDondritics确定受感染的APP/PS1小鼠的疾病发作时的HIV-NCI严重程度 损伤，凋亡，应用程序加工和淀粉样病理学（C）通过生态感染进行类似的研究 表达各种人性化AD基因并为进一步研究选择一个负载模型的负载模型2） 使用APP/PS1小鼠和一只负载应变，在EcoHIV中进行下一代RNA测序（RNA-SEQ） 感染小鼠到达HIV疾病状态后（a）从海马（HPC），前额叶产生转录组 皮层（PFC）和纹状体（Str），并定义与记忆缺陷有关的生物学过程 由HIV和OAβ共同引起； b）在HPC和Str提取物中通过RT-QPCR确认一些基因调制或通过 在大脑部分中进行免疫染色； c）在HPC中进行有限的核-RNA-seq分析以分配改变的HIV- OAβ的过程/转录本针对特定细胞类型。 3）研究负责促进HIV-的分子机制 NCI发病机理在小鼠中自然产生的人OAβ的亚临床水平。 （a）两者既是 HIV和Aβ干扰Wnt信号传导并引起树突修剪，研究髓样细胞的HIV感染如何作用 在树突完整性中aβ的Wnt功能失调。 b）由于Ecohiv下调Camkii和Creb 在研究中，在CREB在突触增强中的CREB作用的OAβ失调中，潜在的Aβ-HIV收敛。 研究将包括中度和晚期AD小鼠的生态感染，学习和记忆测试，HPC 长期增强，HPC突触跨性完整性，凋亡，应用程序加工和淀粉样蛋白病理学 系统和脑HIV伯伦斯，小鼠脑的生物信息学和选择细胞类型。