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HIV和阿尔茨海默病(AD)实验室之间合作项目的重新提交，以 研究艾滋病毒感染和AD标志淀粉样蛋白β(Aβ)在促进记忆方面的潜在协同作用 减损。接受抗逆转录病毒治疗的HIV患者中有一半出现神经认知障碍(NCI)，尽管比例较低 艾滋病毒的脑部负担。年龄是影响NCI进展的最一致的因素。我们复制了HIV-NCI 感染EcoHIV的常规小鼠的发病机制，一种嗜鼠的HIV。MPI项目，阿兰西奥博士 报道称，非突触毒性剂量的外源性寡聚体Aβ(OAβ)和Tau是AD的另一个标志， 在小鼠突触功能障碍和记忆障碍中协同作用，提示AD蛋白具有致病作用 在其亚临床浓度下的潜在性。我们修改后的初步结果表明，这种合作 多种形式的EcoHIV和OAβ，包括感染EcoHIV后的AD小鼠模型认知前 拒绝。模型包括转基因APP/PS1家族性AD小鼠模型(FAD)和两个晚发性AD模型 (LOAD)表达人源化AD蛋白的小鼠模型。我们认为艾滋病毒和亚临床骨性关节炎β过程 在扰乱突触可塑性方面进行合作，以加剧HIV-NCI，而不仅仅是每种因素。具体目标 目的是：1)在FAD和LOAD小鼠模型发病前表征增强的HIV-NCI致病机制 AD症状。(A)优化临床前APP/PS1小鼠因感染EcoHIV而出现记忆缺陷的情况；(B) 用海马LTP、突触树突测定感染APP/PS1小鼠发病时HIV-NCI的严重程度 损伤、细胞凋亡、APP加工和淀粉样蛋白病理(C)EcoHIV感染 加载表达各种人源化AD基因的模型鼠，并选择一种加载模型进行进一步研究2) 利用APP/PS1小鼠和一个负载株，在EcoHIV中进行下一代RNA测序(RNA-seq) 感染HIV的小鼠在达到HIV疾病状态时(A)从海马体(HPC)、前额叶产生转录组 皮层(PFC)和纹状体(STR)，并定义与记忆缺陷特别相关的生物过程 由HIV和OAβ共同引起；B)通过RT-QPCR证实HPC和STR提取物中的某些基因调控或 脑切片中的免疫染色；以及C)在HPC中进行有限的核-RNA-SEQ分析，以确定改变的HIV- OAβ对特定类型的细胞进行加工/转录。3)研究促进艾滋病毒感染的分子机制- 自然产生的亚临床水平的人骨关节炎β在小鼠中的致病机制。(A)由于双方 艾滋病病毒和Aβ干扰WNT信号并导致树突状细胞修剪，检查艾滋病病毒感染髓系细胞的方式 Aβ在树突状细胞完整性中对Wnt功能的失调。B)由于EcoHIV下调CaMKII和CREB的表达 在小鼠中，研究Aβ与艾滋病病毒在骨性关节炎中的潜在会聚，β在突触加强中的作用失调。 研究将包括中晚发型AD小鼠的EcoHIV感染，学习和记忆测试，HPC 长时程增强、HPC突触树突完整性、细胞凋亡、APP加工和淀粉样蛋白病理 系统和大脑的艾滋病毒负担，小鼠大脑的生物信息学和选定的细胞类型。