Project 4 (Pitts)-Cholinergic and amyloid alteration in mild cognitive impairment

项目 4 (Pitts)-轻度认知障碍中的胆碱能和淀粉样蛋白改变

• 批准号: 10427160
• 负责人: Milos D Ikonomovic
• 金额: $ 37.62万
• 依托单位: ST. JOSEPH'S HOSPITAL AND MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427160
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Anterior; Attenuated; Autopsy; Basal Nucleus of Meynert; Binding; Biochemistry; Biological Assay; Brain; Brain region; Case Study; Clinical; Cognition; Cognitive; Collaborations; Data; Dementia; Denervation; Disease; Disease Progression; Down-Regulation; Drug Targeting; Elderly; Enzyme-Linked Immunosorbent Assay; Evaluation; Exhibits; Functional Magnetic Resonance Imaging; Glutamates; Goals; Image; Immunofluorescence Microscopy; Immunohistochemistry; Impaired cognition; In Vitro; Ligands; Liquid Chromatography; Measures; Messenger RNA; Molecular Conformation; Morphology; Neurobiology; Neuronal Plasticity; Neuropsychology; Neurotransmitters; Onset of illness; Pathology; Pharmacotherapy; Positron-Emission Tomography; Presynaptic Terminals; Proteins; Proteomics; Resistance; Study Subject; Synapses; Synaptosomes; System; Testing; Tissues; Tracer; Translational Regulation; Universities; Up-Regulation; amyloid pathology; cholinergic; cingulate cortex; cognitive testing; connectome; cytokine; enzyme activity; frontal lobe; imaging study; insight; mild cognitive impairment; nerve supply; neural circuit; neurochemistry; neuroinflammation; neuropathology; neurotransmitter release; new therapeutic target; novel; novel therapeutics; pre-clinical; preservation; prevent; prodromal Alzheimer' s disease; religious order study; resilience; response; tandem mass spectrometry; tau Proteins

Project Summary/Abstract: Project 4 (University of Pittsburgh) Defining mechanisms that underlie brain resilience to Alzheimer’s disease (AD), the discordance between normal cognition and substantial AD pathology, which occurs in preclinical AD, will provide insights into novel therapeutic targets to prevent dementia. To address this concept, we propose to investigate alterations in neurotransmitter systems and synaptic proteins within the default mode network (DMN), a cortical connectome involving the precuneus (PreC), posterior cingulate cortex (PCC), and frontal cortex (FC), which is prone to amyloid pathology and functional connectivity changes in preclinical and prodromal [mild cognitive impairment, (MCI)]. Project 4 demonstrated a loss of synapses within DMN regions in early AD, but not in MCI compared to subject with no cognitive impairment (NCI). In contrast, we observed upregulated cholinergic activity in FC, but not in the PreC compared to glutamatergic denervation in both regions in MCI. This suggests that a DMN region-specific cholinergic neuroplasticity response, may contribute to brain resilience. Whether similar mechanism(s) occur in preclinical AD is of key importance for drug target discovery. Neuropsychological and neuropathological evaluation of Rush Religious Order Study subjects provides a unique opportunity to investigate compensatory synaptic and neurotransmitter responses associated with resilience in conjunction with AD pathology in NCI with low (LP-NCI) or high (HP-NCI) pathology, MCI and AD. Aim 1A will use confocal immunofluorescence microscopy with unbiased stereology to determine whether different neurochemically- defined synaptic terminals within the DMN conectome are resilient or vulnerable in HP-NCI, MCI, and AD relative to LP-NC. We will correlate these findings with cognitive test scores across groups. Aim 1B will use a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted proteomic assay to determine whether different synaptic proteins within the DMN interactome are resilient or vulnerable in same cases. Aim 2 will determine whether AD neuropathology in the DMN interactome moderates the relationship between synaptic and cognitive measures, by quantifying Tau and amyloid concentrations and pathology in the DMN in the same Aim 1 cases. Aim 3 will examine whether markers of neuroinflammation moderate the relationship between synaptic loss and cognition in the DMN using the same Aim 1 and Aim 2 cases. The translational value of Project 4 is highlighted by our use of in vitro binding assays with tritiated ligands for Tau and amyloid PET imaging, in the same brain regions analyzed for quantitative biochemistry of Tau, amyloid and synaptic markers. The proposed studies will provide pivotal data needed to understand the mechanisms underlying circuit-specific resilience or vulnerability to AD pathology in the preclinical stage of the disease and provide insight into potential new drug therapies.

项目摘要/摘要：项目 4（匹兹堡大学） 定义大脑对阿尔茨海默病（AD）的恢复能力的机制， 正常认知和临床前 AD 中发生的实质性 AD 病理学将为新奇的认知提供见解 为了解决这个概念，我们建议研究预防痴呆症的治疗目标。 默认模式网络 (DMN)（一种皮质连接组）内的神经递质系统和突触蛋白 涉及楔前叶 (PreC)、后扣带皮层 (PCC) 和额叶皮层 (FC)，容易发生 临床前和前驱期的淀粉样蛋白病理学和功能连接变化[轻度认知障碍， (MCI)]。项目 4 证明了 AD 早期 DMN 区域内的突触丢失，但与 MCI 相比则没有。 相比之下，我们观察到 FC 中的胆碱能活性上调。 但与 MCI 中两个区域的谷氨酸去神经支配相比，PreC 中没有，这表明 DMN 存在。 区域特异性胆碱能神经可塑性反应，可能有助于大脑恢复能力。 临床前 AD 中发生的机制对于药物靶点发现至关重要。 Rush Religious Order 研究对象的神经病理学评估提供了一个独特的机会 研究与弹性相关的代偿性突触和神经递质反应 对于具有低（LP-NCI）或高（HP-NCI）病理的NCI中的AD病理，MCI和AD将使用共聚焦。 具有公正体视学的免疫荧光显微镜，以确定是否存在不同的神经化学- DMN 连接体中定义的突触末端在 HP-NCI、MCI 和 AD 中具有弹性或脆弱性 相对于 LP-NC，我们将使用 Aim 1B 将这些发现与各组的认知测试分数相关联。 新型液相色谱-串联质谱 (LC-MS/MS) 靶向蛋白质组测定法可确定 DMN 相互作用组中的不同突触蛋白在相同情况下是否具有弹性或脆弱性。 2 将确定 DMN 相互作用组中的 AD 神经病理学是否调节两者之间的关系 通过量化 DMN 中的 Tau 和淀粉样蛋白浓度和病理学来进行突触和认知测量 目标 1 的情况相同，目标 3 将检查神经炎症标志物是否调节这种关系。 使用相同的目标 1 和目标 2 案例在 DMN 中突触丢失和认知之间进行比较。 项目 4 的价值通过我们使用 Tau 和淀粉样蛋白的氚化配体的体外结合测定来凸显 PET 成像，在同一大脑区域分析 Tau、淀粉样蛋白和突触的定量生物化学 拟议的研究将提供了解潜在机制所需的关键数据。 在疾病的临床前阶段，特定回路对 AD 病理的恢复力或脆弱性，并提供 深入了解潜在的新药疗法。