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Age-Associated Lipidomic Changes in Alzheimer's Disease

阿尔茨海默氏病与年龄相关的脂质组学变化

基本信息

批准号：
10402025
负责人：
JAN Krzysztof BLUSZTAJN
金额：
$ 40.94万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402025
关键词：
Address Age Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Autopsy Biological Biological Markers Blood Brain Clinical Clinical Data Cognitive Data Data Analyses Data Set Dementia Development Diagnosis Disease Disease Progression Docosahexaenoic Acids Enzymes Epidemiology Food Framingham Heart Study Frequencies Functional disorder Future Genes Goals High Prevalence Human Impaired cognition Lecithin Life Lipids Membrane Molecular Molecular Abnormality Neuroglia Neurons Neuropsychology Normal Range Participant Pathogenesis Pathologic Patients Phosphatidylethanolamine N-Methyltransferase Phospholipid Metabolism Plasma Questionnaires Resources Risk Factors Role Sampling Science Specimen Testing Time age related biobank brain tissue clinical infrastructure design effective therapy interdisciplinary approach lipid metabolism lipidome lipidomics mild cognitive impairment mouse model prevent programs study population targeted treatment

项目摘要

Studies proposed in this application are designed to develop an understanding of the molecular and cellular basis for age-related changes in lipid metabolism that impact the development of Alzheimer's disease (AD). To achieve this goal we will use a cross-disciplinary approach that will combine unique sets of clinical data and human biospecimens together with mechanistic hypotheses testing using a mouse model of AD with a relevant targeted genetic abnormality in phospholipid metabolism. There is strong evidence that phospholipid metabo- lism is abnormal in AD brain and there are data indicating that prodromal and frank clinical AD have correlates in the blood plasma lipidome that include apparent abnormalities of the turnover of phosphatidylcholine (PC) – a major constituent of all biological membranes, including those in neurons and glial cells. This is reflected by reduced plasma levels of certain molecular species of PC containing eicosapentaenoic- [EPA, 20:5n-3] and docosahexaenoic acid [DHA, 22:6n-3] in AD. Together, the data suggest the hypothesis that AD pathophysiol- ogy may be characterized by lipidomic abnormalities that occur early in the disease and encompass both the periphery (as reflected by plasma lipidomic changes) and the brain. However, heretofore it has not been possi- ble to address this idea directly due to the lack of an appropriately optimized scientific and clinical infrastructure that incorporates blood and brain samples. We propose to test this hypothesis by interdisciplinary approaches that will employ sets of data and biorepositories of plasma and postmortem brain tissue derived from the par- ticipants of the Framingham Heart Study (FHS) population. The FHS has epidemiology of dementia and brain donation programs (over 200 brains available), resulting in longitudinal clinical and neuropsychological data for subjects whose diagnoses range from cognitively intact to mild cognitive impairment to dementia. The neuro- pathological diagnoses of these subjects range from normal to advanced AD. The FHS has food frequency questionnaire data and has collected plasma samples longitudinally over time from these subjects, making it an optimal resource to identify abnormalities in the metabolism of lipids, associated with cognitive impairment and AD pathology, that may serve as biomarkers and targets for therapy. The polyunsaturated species of PC (such as PC-DHA) are primarily synthesized by the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). PEMT abnormalities reduce plasma PC-DHA concentrations in humans and have been associated with increased risk of AD. Therefore, abnormal PEMT activity may contribute to AD pathophysiology. We pro- pose the following aims: 1) To identify lipidomic- and PEMT activity changes associated with age and AD de- velopment in brain tissue; 2) To determine lipidomic profiles of serial, stored plasma samples obtained in life from the above subjects, and correlate the plasma lipidomic data with the information obtained in Aim 1 and 3) To determine the effect of PEMT activity and PC-DHA levels on the development of AD-like pathology in AD model mice with 2, 1, or 0 copies of the Pemt gene, for mechanistic hypothesis testing.

本申请中提出的研究旨在了解分子和细胞年龄相关的脂质代谢变化的基础，影响阿尔茨海默病（AD）的发展。到为了实现这一目标，我们将采用跨学科的方法，结合联合收割机独特的临床数据集，人类生物标本以及使用AD小鼠模型进行的机制假设检验，磷脂代谢的靶向遗传异常。有强有力的证据表明磷脂代谢- 在AD脑中，lism是异常的，并且有数据表明前驱和坦率的临床AD具有相关性，在血浆脂质组中，包括磷脂酰胆碱（PC）周转的明显异常，所有生物膜的主要组成部分，包括神经元和神经胶质细胞。这反映在某些含二十碳五烯酸的PC分子种类的血浆水平降低[EPA，20：5 n-3]，二十二碳六烯酸[DHA，22：6 n-3]。总之，这些数据表明AD病理生理学- OGY的特征可能是在疾病早期发生的脂质组学异常，外周（如血浆脂质组学变化所反映的）和大脑。然而，迄今为止，它还没有可能- 由于缺乏适当优化的科学和临床基础设施，包含血液和大脑样本我们建议通过跨学科的方法来检验这一假设这将采用数据集和血浆和死后脑组织的生物储存库， FHS（Fragrance Heart Study）人群。FHS有痴呆症和大脑的流行病学捐赠计划（超过200个大脑可用），导致纵向临床和神经心理学数据，诊断范围从认知完整到轻度认知障碍到痴呆的受试者。神经- 这些受试者的病理诊断范围从正常到晚期AD。FHS有食物频率调查问卷数据，并收集了血浆样本纵向随着时间的推移，从这些受试者，使它识别与认知障碍相关的脂质代谢异常的最佳资源和AD病理学，其可用作治疗的生物标志物和靶标。PC的多不饱和物种 (such作为PC-DHA）主要由磷脂酰乙醇胺N-甲基转移酶合成（PEMT）。PEMT异常会降低人类血浆PC-DHA浓度， AD的风险增加。因此，异常的PEMT活性可能有助于AD的病理生理学。我们支持- 提出以下目的：1）确定与年龄和AD去相关的脂质组学和PEMT活性变化， 2）测定生活中获得的系列储存血浆样品的脂质组学特征并将血浆脂质组学数据与目标1和3中获得的信息相关联）确定PEMT活性和PC-DHA水平对AD中AD样病理学发展的影响具有2、1或0个拷贝的Pemt基因的模型小鼠，用于机理假设检验。