Role of microglia in cognitive resilience to AD

小胶质细胞在 AD 认知弹性中的作用

• 批准号: 10649062
• 负责人: Anna Fracassi
• 金额: $ 32万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649062
• 关键词: ANXA5 gene; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Amyloid beta-Protein; Autopsy; Axon; Binding; Biological Assay; Brain; Cd68; Cell Nucleus; Cell surface; Clinical; Cognitive; Cognitive deficits; Creativeness; DLG4 gene; Data; Dementia; Development; Disease; Eating; Event; Excision; Flow Cytometry; Fostering; Functional disorder; Future; Genes; Genetic study; Goals; Health; Hippocampus; Histopathology; Human; Hyperactivity; Impaired cognition; Individual; Lead; Ligands; Ligation; Lysosomes; Maintenance; Mediating; Mediator; Memory impairment; Microglia; Mission; Molecular; Morphology; Mutation; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathologic; Pathway interactions; Persons; Phagocytes; Phagocytosis; Phenotype; Phosphatidylserines; Population; Process; Public Health; Research; Risk; Role; Sampling; Senile Plaques; Signal Transduction; Stains; Structure; Synapses; Synaptosomes; TREM2 gene; TYROBP gene; Testing; United States National Institutes of Health; Variant; Western Blotting; aged; axon injury; demented; expectation; frontal lobe; improved; injured; innovation; insight; loss of function; neuron loss; neuropathology; non-demented; novel; novel therapeutics; postsynaptic; receptor; resilience; superresolution microscopy; synaptic function; therapeutically effective; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common form of dementia characterized by neuronal loss and synaptic dysfunction, and histopathologically hallmarked by the presence of amyloid plaques and neurofibrillary tangles. The correlation between histopathology and dementia has been challenged in the past decade by the emergence of a group of individuals who remain cognitively intact despite the presence of plaques and tangles consistent with clinically symptomatic AD. The existence of these individuals, here referred to as Non-Demented with AD Neuropathology (NDAN) suggests that there is a natural way for the human brain to escape dementia. Understanding the underlying molecular and cellular mechanisms of resilience (the main objective of the present project) may help the development of innovative treatment concepts based on inducing cognitive resilience in anyone challenged by AD neuropathology. We present compelling preliminary results that support our hypothesis that efficient TREM2-driven microglial phagocytosis underlies structural integrity and functionality of synapses in NDAN, thus protecting from ensuing cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: testing whether high expression levels of microglial TREM2 are associated with phagocytosis of damaged synapses around amyloid plaques in NDAN subjects, and evaluating the presence of variants of TREM2 gene in NDAN subjects as a function of synaptic resilience. This present project is highly significant because the proposed studies will establish TREM2 phagocytic microglia as a key player in the maintenance of synaptic integrity. The successful completion of the aims will provide insight into molecular and cellular mechanisms underlying synaptic resilience in relation to microglia activity in NDAN individuals revealing new targets for future development of innovative treatment concepts based on inducing cognitive resilience in individuals challenged by AD neuropathology. The proposed project will improve our scientific understanding of how damaged synapses removal is mediated by TREM2 phagocytic microglia contributing to synaptic integrity in NDAN.

项目概要/摘要 阿尔茨海默病 (AD) 是最常见的痴呆症，其特征是神经元损失和突触丧失 功能障碍，组织病理学上以淀粉样斑块和神经原纤维缠结的存在为特征。 组织病理学与痴呆之间的相关性在过去十年中受到了新疾病的挑战 尽管存在一致的斑块和缠结，但仍保持认知完整的一组个体 具有临床症状的 AD 患者的存在，这里称为非痴呆 AD 患者。 神经病理学（NDAN）表明，人类大脑有一种自然的方式来逃避痴呆症。 了解弹性的潜在分子和细胞机制（本研究的主要目标 项目）可能有助于基于诱导认知弹性的创新治疗概念的发展 任何受到 AD 神经病理学挑战的人。 我们提出了令人信服的初步结果，支持我们的假设，即有效的 TREM2 驱动的小胶质细胞 吞噬作用是 NDAN 中突触结构完整性和功能的基础，从而防止 我们将通过追求以下具体目标来检验我们的中心假设：检验 小胶质细胞TREM2的高表达是否与受损细胞的吞噬作用有关 NDAN 受试者中淀粉样斑块周围的突触，并评估变体的存在 NDAN 受试者中的 TREM2 基因作为突触弹性的函数。 本项目非常重要，因为拟议的研究将建立 TREM2 吞噬小胶质细胞 作为维持突触完整性的关键角色，目标的成功完成将提供。 深入了解突触弹性与小胶质细胞活动相关的分子和细胞机制 NDAN 个人揭示了基于以下内容的创新治疗概念未来发展的新目标 诱导受到 AD 神经病理学挑战的个体的认知弹性。拟议的项目将改善。 我们对 TREM2 吞噬小胶质细胞如何介导受损突触去除的科学理解 有助于 NDAN 中突触的完整性。