NEURONAL & VASCULAR PATHOBIOLOGY IN ALZHEIMER'S DISEASE

该项目重点关注新发现的 AD 病理学特征，与散发性 AD (SAD) 和血管危险因素的作用特别相关。总体目标是检验以下假设：内吞途径 (EP) 和溶酶体系统 (LS) 异常（包括 SAD 大脑中迄今已证实的最早的病理变化）主要参与 SAD 中的淀粉样蛋白生成和神经变性，并且是 AD 中血管和实质病理学之间的关键联系。该计划的主要目标是通过开发改进的 AD（特别是 SAD）和血管病理学小鼠模型，并对这些模型应用生化、细胞生物学、形态测量和体内 MR 成像方法，阐明 AD 的潜在细胞机制。第一个项目研究神经元内吞作用的异常和早期内体蛋白酶运输的增加，并将分析纯化的内体部分与疾病发作和进展的关系。模拟 EP 和蛋白酶运输改变的转染细胞以及转基因和突变小鼠将被表征，以确定这些异常如何影响 Abeta 的形成和清除以及神经元和血管内皮的存活。另一个项目测试了神经元 LS 激活促进细胞萎缩和神经变性的假设。与其他 AD 神经病理学和 APOE 基因型相关的 LS 激活的发生和进展将在 SAD 大脑中确定。将在选择性调节的转基因 FAD 小鼠中评估 LS 激活的前因及其与神经病理学的关系。将定义溶酶体介导的细胞死亡的潜在机制。另一个项目，脑淀粉样血管病和人类 APOE 的缺血模型和转基因小鼠模型将用于阐明血管损伤和 ApoE 同型如何调节 EP 和 LS 异常并促进 AD 神经病理学。 Abeta 清除率将在 AD 和血管小鼠模型中进行体内研究，并在人类和小鼠 BBB 器官模型中进行体外研究。最后一个项目，纵向 MR 成像将应用于转基因小鼠模型，以表征渐进性 β-淀粉样蛋白沉积对大脑结构和功能的影响。这些测量可直接应用于人类成像研究和其他小鼠模型，包括脑区域体积、脑灌注（血流量）和扩散定量神经病理学。预计该计划将建立改进的动物模型用于药物发现，通过 MR 成像推进临床诊断，并定义新的发病机制的细胞机制，这将成为 AD 治疗的基础。

This program focuses on newly identified features of AD pathobiology, having particular relevance to sporadic AD (SAD) and the role of vascular risk factors. The overall goal is to test the hypothesis that endocytic pathway (EP) and lysosomal system (LS) abnormalities, which include the earliest pathological changes yet demonstrated in SAD brain, are centrally involved in amyloidogenesis and neurodegeneration in SAD and are a critical link between vascular and parenchymal pathology in AD. The Program's main objectives are to elucidate underlying cellular mechanisms in AD by developing imporoved mouse models of AD, particular SAD, and of vascular pathology and by applying biochemical, cell biological, morphometric, and in vivo MR imaging approaches to these models. The first project investigate abnormalities of neuronal endocytosis and increased protease trafficking to early endosomes and purified endosome fractions will be analyzed in relation to disease onset and progression. Transfected cells and transgenic and mutant mice that model EP and protease trafficking alterations will be characterized to establish how these abnormalities influence Abeta formation and clearance and the survival of neurons and vascular endothelia. Another project tests the hypothesis that neuronal LS activation promotes cell atrophy and neurodegeneration. The onset and progression of LS activation in relation to other AD neuropathology and APOE genotype will be determined in SAD brain. Antecedents to LS activation and relationships to neuropathology will be evaluated in transgenic FAD mouse selectively modulated. Mechanisms underlying lysosome- mediated cell death will be defined. Another project, ischemia models and transgenic mouse models of cerebral amyloid angiopathy and of human APOE will be used to clarify how vascular injury and ApoE isotype modulate EP and LS abnormalities and promote AD neuropathology. Abeta clearance will be studied in vivo in AD and vascular mouse models and in vitro in organotypic models of the human and mouse BBB. The last project, longitudinal MR imaging will be applied to transgenic mouse models to characterize the effects of progressive beta-amyloid deposition on brain structure and function. The measures, which are directly translatable to human imaging studies and other mouse models, including brain regional volumes, cerebral perfusion (blood flow), and diffusion quantitative neuropathology. It is anticipated that this Program will establish improved animal models for drug discovery, advance clinical diagnosis by MR imaging, and define novel cellular mechanisms of pathogenesis that will be the basis for AD therapies.