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

项目摘要

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.

项目总结

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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.