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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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

项目摘要

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病 (AD) 实验室之间的合作项目的重新提交研究 HIV 感染和 AD 标志性淀粉样蛋白 β (Aβ) 在促进记忆方面的潜在协同作用接受抗逆转录病毒治疗的艾滋病毒患者中有一半会出现神经认知障碍（NCI），尽管其水平较低。 HIV 脑负担。年龄是影响 NCI 进展的最一致的因素。感染 EcoHIV 的传统小鼠的发病机制，MPI 项目，Arancio 博士，报道称，非突触毒性剂量的外源寡聚 Aβ (oAβ) 和 Tau（AD 的另一个标志），在小鼠的突触功能障碍和记忆障碍中协同作用，表明 AD 蛋白具有致病性我们修订后的初步结果显示了它们之间的这种合作。 EcoHIV 和 oAβ 具有多种形式，包括在 AD 小鼠模型认知之前的 EcoHIV 感染之后这些模型包括家族性 AD (FAD) 转基因 APP/PS1 小鼠模型和两种迟发性 AD 模型。 (LOAD) 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，加剧 HIV-NCI 超出每种药物单独作用的范围。目的是： 1) 在 FAD 和 LOAD 小鼠模型发病前表征增强的 HIV-NCI 发病机制 (A) 优化临床前 APP/PS1 小鼠中 EcoHIV 感染引起的记忆缺陷；通过海马 LTP、突触树突确定受感染 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学 (C) 通过 EcoHIV 感染进行类似的研究表达多种人源化AD基因的LOAD模型小鼠并选择一种LOAD模型进行进一步研究2) 使用 APP/PS1 小鼠和一种 LOAD 品系，在 EcoHIV 中进行下一代 RNA 测序 (RNA-seq) 感染 HIV 的小鼠在达到 HIV 疾病状态后 (A) 从海马 (HPC)、前额叶生成转录组皮质（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 HPC 和 STR 提取物中的 RT-QPCR 或通过脑切片的免疫染色；以及 C) 在 HPC 中进行有限的核 RNA 测序分析，以分配改变的 HIV- oAβ 对特定细胞类型的加工/转录 3) 研究促进 HIV-的分子机制。小鼠体内自然产生亚临床水平的人类 oAβ 的 NCI 发病机制 (A)。 HIV 和 Aβ 干扰 wnt 信号传导并导致树突修剪，检查 HIV 感染骨髓细胞的工作原理 Aβ 导致树突完整性中 Wnt 功能失调 B) 因为 EcoHIV 下调 CaMKII 和 CREB。在小鼠中研究了潜在的 Aβ-HIV 收敛在 oAβ 失调中 CREB 在突触强化中的作用。研究将包括中度和晚期 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学系统和大脑艾滋病毒负担、小鼠大脑和选择细胞类型的生物信息学。