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.

项目摘要/摘要 尽管抗逆转录病毒疗法的结合出现以来，近25年了，但多达50％的艾滋病毒患者 一生中将经历某种程度的认知障碍。这些与HIV相关的神经系统 疾病（手）是通过中央艾滋病毒浸润引起的多种神经毒性作用驱动的 神经系统（CNS）。虽然手动神经病理已经被理解了多年，但特定的 手动认知功能障碍支撑的机制尚不清楚。游离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已知 促进广泛的细胞事件，从而导致CNS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如何引起这些影响对于未来至关重要 为艾滋病毒感染者开发治疗学。在组成性表达的手的鼠标模型中 GP120在CNS（GP120TG）中，我们的实验室确定gp120 perturbs pro-神经营养蛋白处理和 上调P75NTR，一种促凋亡的促尿营养蛋白受体。我们最近的工作还表明了树突状 脊柱因GP120驱动的神经营养蛋白受体的破坏而导致简化或损失的风险增加 环境。 P75NTR在这种效果中的核心作用得到了生化，组织学的部分营救的支持 当去除p75NTR时，较老的GP120TG小鼠的行为异常。但是，失去脆弱的人 基底前脑（BFCN）中的胆碱能神经元的种群，该神经元高度表达P75NTR 在多种神经退行性疾病中观察到变性可以更好地解释认知障碍 手比广泛的突触损失。朝这个方向的初步数据表明，较老的GP120TG小鼠已经受损 条件恐惧的灭绝，一种取决于BFCN完整性的行为。我假设GP120表达驱动器 这些BFCN的变性通过涉及局部神经营养环境中断的机制。 为了确认GP120表达是否会破坏前脑中神经营养蛋白的处理，我将牺牲老化 gp120转基因小鼠（以及对照）并评估前脑生长因子（PRONGF）和 NGF以及两个催化其转化率的蛋白酶（AIM 1A）。从这些小组中，我也将 BFCN标记的前脑和免疫抑制剂评估胆碱能细胞群和BFCN的测量 复杂性（AIM 1B）。来自BFCN靶向区域的突触体将确定是否表达 GP120TG小鼠的胆碱能神经支配降低（AIM 1C）。最后，我将评估前脑的减少 该模型中的灰质密度和septohappocampal道的完整性（BFCN纤维）通过磁性 共振（MR）成像方法（AIM 2）。我假设老化的GP120TG小鼠将显示出改变的前脑 神经营养环境将与降低的BFCN计数 /复杂性相对应，而前脑则降低 灰质密度 / septohappocampal道的完整性。在整个提议的培训中，我将获得专业知识 立体学和MR成像，它们在神经退行性疾病领域具有很高的翻译价值。