Investigation of Basal Forebrain Degeneration in HIV-Associated Neurocognitive Disorder

HIV 相关神经认知障碍中基底前脑变性的调查

• 批准号: 10327006
• 负责人: Andrew Speidell
• 金额: $ 3.33万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327006
• 关键词: Investigation; Basal; Forebrain; Degeneration; HIV

PROJECT SUMMARY/ABSTRACT Despite nearly 25 years since the advent of combined antiretroviral therapy, up to 50% of people living with HIV will experience some degree of cognitive impairment in their lifetimes. These HIV-associated neurological disorders (HAND) are driven through a variety of neurotoxic effects resulting from HIV infiltration of the central nervous system (CNS). While the neuropathology of HAND has been understood for years, the specific mechanisms underpinning cognitive dysfunction in HAND individuals remain unclear. Free HIV viral proteins are known to possess independent neurotoxic effects. Of these molecules, the envelope protein gp120, is known to facilitate a wide range of cellular events which result in simplification / apoptosis of neurons in CNS regions critical for higher cognitive function. Understanding how gp120 may elicit these effects is critical for the future development of therapeutics for those living with HIV. In a mouse model of HAND which constitutively expresses gp120 in the CNS (gp120tg), our lab has established that gp120 perturbs pro-neurotrophin processing and upregulates p75NTR, a pro-apoptotic proneurotrophin receptor. Our recent work has also shown that dendritic spines are at increased risk for simplification or loss due to gp120-driven disruption of the neurotrophin-receptor environment. A central role for p75NTR in this effect is supported by partial rescue of biochemical, histological, and behavioral abnormalities in older gp120tg mice when p75NTR is removed. However, loss of a vulnerable population of cholinergic neurons in the basal forebrain (BFCNs) which highly express p75NTR and whose degeneration is observed in multiple neurodegenerative diseases may better explain cognitive impairments in HAND than broad synapse loss. Preliminary data in this direction indicates that older gp120tg mice have impaired extinction of conditioned fear, a behavior dependent on BFCN integrity. I hypothesize gp120 expression drives degeneration of these BFCNs through a mechanism involving disruption of the local neurotrophic environment. To confirm whether gp120 expression disrupts neurotrophin processing in the forebrain, I will sacrifice aged gp120 transgenic mice (and controls) and assess forebrain expression of pro nerve growth factor (proNGF) and NGF, as well as two proteases which catalyze their conversion (Aim 1a). From these groups, I will also section the forebrain and immunostain for BFCNs markers to assess cholinergic cell population and measures of BFCN complexity (Aim 1b). Synaptosomes from BFCN-targeted regions will determine if expression of markers of cholinergic innervation are decreased in gp120tg mice (Aim 1c). Finally, I will assess decrements in forebrain gray matter density and septohippocampal tract integrity (BFCN fibers) in this model through a magnetic resonance (MR) imaging approach (aim 2). I hypothesize that aged gp120tg mice will display an altered forebrain neurotrophic environment, which will correspond with reduced BFCN count / complexity and decreased forebrain gray matter density / septohippocampal tract integrity. Throughout the proposed training, I will gain expertise in stereology and MR imaging, which have high translational value in the field of neurodegenerative diseases.

项目概要/摘要 尽管联合抗逆转录病毒疗法问世已近 25 年，但仍有高达 50% 的艾滋病毒感染者 在他们的一生中会经历一定程度的认知障碍。这些与 HIV 相关的神经系统疾病 疾病 (HAND) 是由 HIV 浸润中枢神经系统引起的各种神经毒性作用驱动的。 神经系统（CNS）。虽然人们对 HAND 的神经病理学了解已有多年，但具体的 HAND 个体认知功能障碍的机制尚不清楚。游离的 HIV 病毒蛋白是 已知具有独立的神经毒性作用。在这些分子中，已知包膜蛋白 gp120 促进广泛的细胞事件，导致中枢神经系统区域神经元的简化/凋亡 对于更高的认知功能至关重要。了解 gp120 如何引发这些影响对于未来至关重要 为艾滋病毒感染者开发治疗方法。在组成型表达 HAND 的小鼠模型中 gp120 在中枢神经系统 (gp120tg) 中，我们的实验室已确定 gp120 会扰乱前神经营养蛋白的加工和 上调 p75NTR，一种促凋亡前神经营养蛋白受体。我们最近的工作还表明，树突状 由于 gp120 驱动的神经营养蛋白受体破坏，脊柱面临着简化或丢失的风险增加 环境。 p75NTR 在这种效应中的核心作用得到了生化、组织学、 当 p75NTR 被去除时，老年 gp120tg 小鼠的行为异常。然而，失去一个脆弱的 基底前脑 (BFCN) 中高度表达 p75NTR 的胆碱能神经元群体 在多种神经退行性疾病中观察到的退行性变可能更好地解释了认知障碍 手比广泛的突触损失。这方面的初步数据表明，老年 gp120tg 小鼠的功能受损 条件性恐惧的消除，这种行为依赖于 BFCN 的完整性。我假设 gp120 表达驱动 通过破坏局部神经营养环境的机制使这些 BFCN 退化。 为了确认 gp120 表达是否会破坏前脑中的神经营养蛋白处理，我将牺牲年龄 gp120 转基因小鼠（和对照）并评估前神经生长因子 (proNGF) 的前脑表达和 NGF 以及两种催化其转化的蛋白酶（目标 1a）。我还将从这些组中划分 前脑和 BFCN 标记物的免疫染色可评估胆碱能细胞群和 BFCN 的测量 复杂性（目标 1b）。来自 BFCN 靶向区域的突触体将确定 BFCN 标记物的表达是否 gp120tg 小鼠的胆碱能神经支配减少（目标 1c）。最后，我将评估前脑的减量 该模型中的灰质密度和隔海马束完整性（BFCN 纤维）通过磁性 共振 (MR) 成像方法（目标 2）。我假设老年 gp120tg 小鼠的前脑会发生改变 神经营养环境，这将对应于 BFCN 计数/复杂性的减少和前脑的减少 灰质密度/隔海马束完整性。在整个拟议的培训中，我将获得以下方面的专业知识 体视学和磁共振成像在神经退行性疾病领域具有很高的转化价值。