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Endoplasmic Reticulum Mitochondrial membranes in Alzheimer's disease

阿尔茨海默病中的内质网线粒体膜

基本信息

批准号：
9484212
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
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9484212
关键词：
Affect Alzheimer&apos s Disease Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Area Attention Award Basic Science Biochemical Brain C-terminal Calcium Cell Line Cell membrane Cell model Cells Cerebellum Cholesterol Cholesterol Esters Cholesterol Homeostasis Cleaved cell Communication Complex Diagnosis Disease 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 Morphology Mus Mutation N-terminal 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 base beta secretase beta-site APP cleaving enzyme 1 career crosslink extracellular follow-up gamma secretase 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 skills stem cell differentiation tau Proteins

项目摘要

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 ß-amyloid (Aß) 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 γ-secretase activity, which processes the amyloid precursor protein (APP) to generate Aß, 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 γ-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 γ-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）的特征是神经元损失，尤其是在皮质和海马中，并伴有脑中含有β-淀粉样蛋白（A β）的细胞外神经炎斑块和由过度磷酸化tau蛋白组成的细胞内神经原纤维缠结的积聚。AD患者还存在其他较少关注的特征，包括异常的胆固醇、磷脂和钙稳态，以及改变的线粒体功能和动力学。早老素-1（PS1）、早老素-2（PS2）和γ-分泌酶活性（其加工淀粉样前体蛋白（APP）以产生AAPs）都主要位于内质网（ER）的一个专门的亚隔室中，该亚隔室与线粒体物理和生化连接，称为内质网相关ER膜（MAM）。MAM参与调节胆固醇和磷脂代谢、钙稳态以及线粒体功能和动力学。最近，我们发现MAM是脂筏样结构域，AD患者的细胞大量上调MAM活性并增加ER线粒体连接，导致胆固醇，磷脂和钙稳态改变，以及线粒体动力学异常，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功能障碍和改变ER-线粒体连接是AD发病机制中的早期致病事件。我们现在提出的研究旨在从基础科学的角度来理解MAM功能，最终目标是将这些知识应用于实践。具体而言，我们将（1）分析MAM在更“AD相关”的细胞和组织中的功能，包括PS缺陷的人神经母细胞瘤细胞、分化为神经元的人诱导多能干细胞以及从PS1敲入小鼠中获得的组织和神经元;（2）分析MAM中早老素和γ-分泌酶相对于其它区室（诸如“本体”ER或质膜）的调节，同时也评估其他组成部分的作用，（例如APH-1、nicastrin、PEN 2）和调节剂（例如，CD 147、GSAP和TMP 21）;以及（3）通过以各种固定距离将ER与线粒体连接，使用新的ER-线粒体“交联”质粒，以便以不依赖早老蛋白的方式模拟ER-线粒体连接。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.

阿尔茨海默氏病与APP相关的C99碎片调节细胞胆固醇的运输。

DOI：
10.15252/embj.2019103791
发表时间：
2020-10-15
期刊：
The EMBO journal
影响因子：
0
作者：
Montesinos J;Pera M;Larrea D;Guardia-Laguarta C;Agrawal RR;Velasco KR;Yun TD;Stavrovskaya IG;Xu Y;Koo SY;Snead AM;Sproul AA;Area-Gomez E
通讯作者：
Area-Gomez E

Mitochondria-associated ER membranes and Alzheimer disease.