NEURONAL & VASCULAR PATHOBIOLOGY IN ALZHEIMER'S DISEASE

本课程的重点是新发现的AD病理生物学特征，特别是与散发性AD （SAD）和血管危险因素的作用相关。总体目标是验证如下假设：内吞途径（EP）和溶酶体系统（LS）异常，包括SAD大脑中最早的病理改变，在SAD的淀粉样变和神经变性中起主要作用，并且是AD的血管和实质病理之间的关键联系。该项目的主要目标是通过开发改进的阿尔茨海默病小鼠模型，特别是SAD和血管病理学模型，并通过对这些模型应用生化、细胞生物学、形态计量学和体内磁共振成像方法，阐明阿尔茨海默病的潜在细胞机制。第一个项目研究神经元内吞作用异常和早期核内体和纯化核内体部分的蛋白酶运输增加，将分析与疾病发生和进展的关系。转染细胞和转基因和突变小鼠模型EP和蛋白酶转运改变将被表征，以确定这些异常如何影响β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激活促进细胞萎缩和神经变性的假设。与其他AD神经病理和APOE基因型相关的LS激活的开始和进展将在SAD脑中确定。LS激活的前因及其与神经病理学的关系将在选择性调节转基因FAD小鼠中进行评估。溶酶体介导的细胞死亡机制将被明确。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。我们将在AD和血管小鼠模型以及人类和小鼠血脑屏障的体外器官型模型中研究Abeta清除。最后一个项目，纵向磁共振成像将应用于转基因小鼠模型，以表征进行性β -淀粉样蛋白沉积对大脑结构和功能的影响。这些测量结果可直接转化为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。预计该项目将建立改进的动物模型，用于药物发现，通过磁共振成像推进临床诊断，并确定新的细胞发病机制，这将成为阿尔茨海默病治疗的基础。

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.