Role of microglia in cognitive resilience to AD

项目摘要/摘要 阿尔茨海默病(AD)是最常见的痴呆形式，其特征是神经元丢失和突触 功能障碍，组织病理学特征为淀粉样斑块和神经原纤维缠结的存在。 在过去的十年里，组织病理学和痴呆症之间的相关性受到了新出现的挑战 指一群个体，尽管存在一致的斑块和缠结，但他们的认知仍然完好无损 有临床症状的阿尔茨海默病。这些个体的存在，在这里被称为非痴呆的AD 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。 理解复原力的潜在分子和细胞机制(目前的主要目标 项目)可能有助于开发基于诱导认知弹性的创新治疗概念 任何受到阿尔茨海默病神经病理学挑战的人。 我们提出了令人信服的初步结果，支持了我们的假设，即有效的TREM2驱动的小胶质细胞 吞噬作用是ndan突触结构完整性和功能的基础，从而保护 随之而来的认知缺陷。我们将通过追求以下具体目标来测试我们的中心假设：测试 小胶质细胞TREM2高表达是否与受损细胞吞噬功能有关 NDAN受试者淀粉样斑块周围的突触，并评估其变体的存在 Ndan受试者TREM2基因与突触弹性的关系。 这一项目非常有意义，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。这些目标的成功完成将提供 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创新治疗概念未来发展的新目标 在受到AD神经病理挑战的个体中诱导认知弹性。拟议中的项目将有所改善 我们对TREM2吞噬小胶质细胞如何介导受损突触移除的科学理解 有助于NDAN中突触的完整性。

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.