Endoplasmic Reticulum Mitochondrial membranes in Alzheimer's disease

阿尔茨海默病中的内质网线粒体膜

• 批准号: 8767203
• 负责人: Estela Area Gomez
• 金额: $ 11.34万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767203
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Animal Model; Area; Attention; Award; Basic Science; Biochemical; Brain; C-terminal; Calcium; Cell Line; Cell membrane; Cells; Cerebellum; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Cleaved cell; Communication; Complex; Diagnosis; Disease; Doctor of Philosophy; Endoplasmic Reticulum; Event; Fibroblasts; Functional disorder; Funding; Future; Goals; Hippocampus (Brain); Homeostasis; Human; Investigation; Knock-in Mouse; Knowledge; Length; Lipids; Measures; Membrane; Membrane Microdomains; Mentorship; Mitochondria; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenesis; Patients; Phenotype; Phospholipid Metabolism; Phospholipids; Plasmids; Process; Regulation; Research Project Grants; Role; Senile Plaques; Source; Specificity; Thinking; Tissues; Up-Regulation; Work; amyloid precursor protein processing; base; beta-site APP cleaving enzyme 1; career; clinically relevant; crosslink; extracellular; follow-up; human tissue; hyperphosphorylated tau; induced pluripotent stem cell; insight; membrane activity; mitochondrial membrane; neuroblastoma cell; neuron loss; nicastrin protein; novel; presenilin; presenilin-1; presenilin-2; public health relevance; secretase; skills; tau Proteins

DESCRIPTION (provided by applicant): Alzheimer disease (AD) is characterized by neuronal loss, especially in the cortex and hippocampus, accompanied by accumulation in the brain of extracellular neuritic plaques containing ¿-amyloid (A¿) and of intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. AD patients also present with other features that have received less attention, including aberrant cholesterol, phospholipid, and calcium homeostasis, and altered mitochondrial function and dynamics. Presenilin-1 (PS1), presenilin-2 (PS2), and ?-secretase activity, which processes the amyloid precursor protein (APP) to generate A¿, are all located predominantly in a specialized subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAM). MAM is involved in the regulation of cholesterol and phospholipid metabolism, calcium homeostasis, and in mitochondrial function and dynamics. Recently, we showed that MAM is lipid raft-like domain and that cells from AD patients have massively upregulated MAM activity and increased ER mitochondrial connectivity, resulting in altered cholesterol, phospholipid and calcium homeostasis, and aberrant mitochondrial dynamics, which may help explain many of the biochemical and morphological features of the disease. Based on these findings, we believe that MAM dysfunction and altered ER-mitochondrial connectivity are early causative events in the pathogenesis of AD. We now propose studies aimed at understanding MAM function from a basic science standpoint, with the ultimate goal of applying this knowledge translationally. Specifically, we will (1) analyze MAM function in cells and tissues that are more "AD-relevant," including PS-deficient human neuroblastoma cells, human induced pluripotent stem cells differentiated into neurons, and tissues and neurons explanted from PS1 knock-in mice; (2) analyze presenilins and ?-secretase regulation in MAM versus other compartments, such as "bulk" ER or the plasma membrane, while also assessing the role of other components (e.g. APH-1, nicastrin, PEN2) and regulators (e.g. CD147, GSAP, and TMP21) of the ?-secretase complex; and (3) understand the role of ER-mitochondrial communication in the pathogenesis of AD, by tethering ER to mitochondria at various fixed distances, using novel ER-mitochondria "crosslinking" plasmids, in order to mimic ER-mitochondrial connectivity in a presenilin-independent manner.

描述（由申请人提供）：阿尔茨海默病（AD）的特征是神经元丧失，特别是在皮层和海马中，伴随着大脑中含有-淀粉样蛋白(A)的细胞外神经斑块和由过度磷酸化的tau蛋白组成的细胞内神经原纤维缠结的积累。AD患者还表现出其他不太受关注的特征，包括异常的胆固醇、磷脂和钙稳态，以及线粒体功能和动力学的改变。早老素-1 （PS1）、早老素-2 （PS2）和？-分泌酶活性，处理淀粉样前体蛋白（APP）生成A¿，都主要位于内质网（ER）的一个专门的亚室中，该亚室在物理和生化上与线粒体相连，称为线粒体相关ER膜（MAM）。MAM参与胆固醇和磷脂代谢、钙稳态以及线粒体功能和动力学的调节。最近，我们发现MAM是脂质筏样结构域，来自AD患者的细胞MAM活性大幅上调，内质网线粒体连通性增加，导致胆固醇、磷脂和钙稳态改变，线粒体动力学异常，这可能有助于解释该疾病的许多生化和形态学特征。基于这些发现，我们认为MAM功能障碍和er -线粒体连通性改变是AD发病的早期致病事件。我们现在建议研究旨在从基础科学的角度理解MAM功能，最终目标是将这些知识应用于翻译。具体来说，我们将(1)分析MAM在与ad更相关的细胞和组织中的功能，包括ps缺陷的人类神经母细胞瘤细胞、分化为神经元的人类诱导多能干细胞，以及从PS1敲入小鼠中外植的组织和神经元；(2)分析早老素和？-分泌酶在MAM中相对于其他区室（如“散装”内质膜或质膜）的调节，同时也评估了其他成分（如APH-1、nicastrin、PEN2）和调节因子（如CD147、GSAP和TMP21）的作用。分泌酶复杂;(3)通过使用新型ER-线粒体“交联”质粒将ER以不同的固定距离拴在线粒体上，以不依赖于临老素的方式模拟ER-线粒体连接，了解ER-线粒体通信在AD发病机制中的作用。