Neuropathology of synapses in AD and ADRD

项目摘要/摘要 虽然其分子机制尚不清楚，但认知功能障碍的解剖学基础 阿尔茨海默病(AD)是突触的损伤和变性。不同脑区神经元的亚群 这些区域可能或多或少对特定类型的侮辱敏感，但分子特征 AD和AD相关痴呆(ADRD)中的突触是有限的，留下了这种选择性和 被广泛使用的小鼠模型对人类状况的保真度尚不清楚。在这里，我们建议填补这些 在衰老和阿尔茨海默病中通过识别分子特征提示或 确认可能调节脆弱性的细胞通路。提议的项目将使用一个 独特的组织资源和我们开发的新技术，并将其与尖端机器相结合 学习(ML)技术，以增强差分信号并实现对潜在因素的更深入了解 选择性神经元的脆弱性或韧性。我们开发的新技术被称为 通过飞行时间或SynTOF进行突触测量，它为多重分子提供了一个无与伦比的机会 对数百万个单一突触事件的分析。我们将建立在初步数据的基础上，这些数据结合了这一新的 用ML方法获得AD突触损伤的新见解的技术，包括转基因 在神经元中区域过度表达淀粉样蛋白(A)β多肽的小鼠模型，并突出了 SynTOF在发现人类突触亚型损伤的分子模式以及评估 小鼠模型在单个突触水平上的保真度。利用我们独特的冷冻保存组织资源 来自参与者的突触准备，具有广泛的临床、遗传和神经病理注释，新颖 和强大的技术，以及强大的计算方法，我们建议检验以下假设 AD和ADRD中的突触损伤是疾病、脑区域和突触亚型特异的，从而突出 治疗干预的新靶点和确定三种常用转基因药物的程度 小鼠系模拟了人类的突触损伤。成功完成后，我们的新资源和 方法将为突触前和突触后亚型特定的损伤机制提供独特的见解 前所未有的规模，并进一步突出了AD和ADRD的新治疗靶点。

PROJECT SUMMARY / ABSTRACT Although its molecular mechanisms remain to be clarified, the anatomic basis of cognitive impairment in Alzheimer's disease (AD) is injury and degeneration of synapses. Subpopulations of neurons in different brain areas may be more or less susceptible to specific types such insults Yet, molecular characterization of synapses in AD and AD–related dementias (ADRD) is limited, leaving the factors underlying this selectivity and the fidelity of widely-used mouse models to the human condition unclear. Here, we propose to fill these important gaps in selective cell vulnerability in aging and AD by identifying molecular signatures to suggest or confirm cellular pathways that may mediate vulnerability. The proposed project will accomplish this using a unique tissue resource and novel technology developed by us, and couple them with cutting-edge machine learning (ML) techniques to enhance differential signals and achieve deeper insights into the factors underlying selective neuron vulnerability or resilience. The novel technology that we have developed is called Synaptometry by Time-of-Flight, or SynTOF, and it provides an unparalleled opportunity for multiplex molecular analysis of millions of single synaptic events. We will build on our preliminary data, which coupled this new technology with ML approaches to gain novel insights into synaptic injury in AD, including in a transgenic mouse model that regionally overexpresses amyloid (A) β peptides in neurons, and which highlight the value of SynTOF in discovering the molecular patterns of injury in human synaptic subtypes, as well as assessing the fidelity of mouse models at the single synaptic level. Drawing on our unique tissue resource of cryopreserved synaptic preparations from participants with extensive clinical, genetic, and neuropathologic annotation, novel and powerful technology, and robust computational approaches, we propose to test the hypothesis that synapse injury in AD and ADRD is disease-, brain region-, and synapse subtype-specific, thereby highlighting new targets for therapeutic intervention and determining the extent to which three commonly used transgenic mouse lines model the synaptic injury of humans. When successfully completed, our novel resources and approach will provide unique insights into pre- and postsynapse subtype-specific mechanisms of injury at unprecedented scale, and further highlight new therapeutic targets for AD and ADRD.