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病（AD）实验室之间的合作项目的重新提交