Mechanistic Basis of the mtDNA Haplogroup J-Alzheimer's Disease Association

mtDNA 单倍群 J-阿尔茨海默病协会的机制基础

• 批准号: 10565875
• 负责人: RUSSELL H. SWERDLOW
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10565875
• 关键词: Address; Affect; Age; Aged, 80 and over; Aging; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Basic Science; Binding; Biological; Biological Assay; Biological Markers; Biology; Blood Platelets; Blood specimen; Brain; Cell Line; Cells; Cellular biology; Clinical; Clinical Sciences; Code; Cognitive; Cohort Studies; Complement; Complex; Cytoplasm; Data; Disease Progression; Etiology; Experimental Designs; Frequencies; Funding Opportunities; Genetic Determinism; Genetic Polymorphism; Genetic Transcription; Genotype; Haplogroup; Human; Hybrids; Individual; Inherited; Kansas; Length; Link; Longevity; Lymphocyte; Measurement; Mediating; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial DNA; Mitochondrial Proteins; Molecular; Onset of illness; Oxidative Stress; Pathology; Peripheral; Persons; Phenotype; Proteins; Qualifying; Research; Respiration; Respiratory Chain; Risk Factors; Role; Senile Plaques; Single Nucleotide Polymorphism; Solid; Testing; Tissues; Travel; Universities; Variant; Whole Blood; age related; aging brain; clinical phenotype; cognitive change; cohort; endophenotype; experimental study; genetic association; genetic variant; human subject; imaging biomarker; insight; protective factors; resilience; telomere

PROJECT SUMMARY Extensive research ties mitochondria to Alzheimer's disease (AD), but how mitochondria contribute to AD risk or progression remains unsettled. Here, we build on new and compelling data that indicate the mitochondrial DNA (mtDNA) haplogroup J occurs in higher frequencies in persons with AD. This finding argues mitochondria independently contribute to AD, and is particularly unexpected as increased haplogroup J frequency paradoxically also occurs in the oldest old. Four specific haplogroup J-defining polymorphisms appear to drive the association; three reside in the mtDNA control region that regulates mtDNA replication and transcription, and the fourth is a non-synonymous ND5 variant. These variants travel together and currently we cannot tell whether the control region variants, the protein-coding variant, or a combination contributes to AD risk. To resolve this and gain new AD mechanistic insight, we propose a synergistic two-aim, bench-and- bedside approach that will extend these genetic associations to functional associations. In Aim 1, we use cytoplasmic hybrid (cybrid) cell lines to define how the haplogroup J variants affect mitochondrial function and integrity. In Aim 2, we use clinical biospecimen and biomarker data to further explore the haplogroup J, AD, and aging nexus. Thus, in addition to advancing our understanding of AD, our mechanistic analysis of haplogroup J effects will also inform how mitochondrial biology relates to aging. These studies will provide insight into mechanisms that cause AD and aging to converge, but also occasionally diverge.

项目摘要 广泛的研究将线粒体与阿尔茨海默氏病（AD）联系起来，但线粒体如何有助于AD 风险或进展仍然不稳定。在这里，我们以新的和引人注目的数据为基础，表明 线粒体DNA（mtDNA）单倍群J发生在AD患者中的较高频率中。这一发现争辩 线粒体独立贡献AD，并且随着单倍群的增加而尤其出乎意料 频率矛盾也发生在最古老的旧。四个特定的单倍群J定义多态性 似乎推动了协会；三个位于调节mtDNA复制和的mtDNA控制区域 转录，第四个是非同义的ND5变体。这些变体一起旅行，目前我们 无法判断控制区域变体，蛋白质编码变体或组合是否有助于AD 风险。为了解决这一问题并获得新的广告机械洞察 将这些遗传关联扩展到功能关联的床边方法。在AIM 1中，我们使用 细胞质杂交（Cybrid）细胞系，以定义单倍群J变体如何影响线粒体功能和 正直。在AIM 2中，我们使用临床生物测量和生物标志物数据进一步探索单倍群J，AD， 和衰老的联系。因此，除了促进我们对AD的理解外，我们对 单倍型J效应还将告知线粒体生物学与衰老的关系。这些研究将提供 深入了解导致AD和衰老融合但偶尔会分歧的机制。

项目成果

A Mitochondrial DNA Haplogroup Defines Patterns of Five-Year Cognitive Change.

• DOI: 10.3233/jad-220298
• 发表时间: 2022
• 期刊: JOURNAL OF ALZHEIMERS DISEASE
• 影响因子: 4
• 作者: Watts, Amber;Chalise, Prabhakar;Hu, Jinxiang;Hui, Dongwei;Pa, Judy;Andrews, Shea J.;Michaelis, Elias K.;Swerdlow, Russell H.
• 通讯作者: Swerdlow, Russell H.