Mitochondrial DNA affects tau phosphorylation in aging and Alzheimer's disease

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-07-01 DOI:10.1002/alz.70390

Riley E. Kemna, Paul J. Kueck, Robyn Honea, Zachary Clark, Michaella Rekowski, Ian Weidling, Hana Mayfield, Casey S. John, Jeffrey Burns, Heather M. Wilkins, Russell Swerdlow, Jill K. Morris

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Abstract

INTRODUCTION

Impaired mitochondrial function is seen in Alzheimer's disease (AD), but its role is unclear. Mitochondrial DNA (mtDNA) supports bioenergetic metabolism, but it is uncertain how it might influence AD neuropathology.

METHODS

We used cytoplasmic hybrid (cybrid) cell lines made from SH-SY5Y cells expressing mtDNA from cognitively healthy (CH), mild cognitive impairment (MCI), or AD individuals to investigate the impact of mtDNA-determined mitochondrial function on amyloid, tau, and neurodegeneration (ATN) markers. Cybrid measurements were correlated with cognition and brain morphometry.

RESULTS

Relative to cybrids expressing mtDNA from CH individuals, MCI and AD cybrids contained more phosphorylated tau-217 (p-tau217), p-tau181, and total tau. Cybrid p-tau217 correlated with plasma p-tau217 from the mtDNA donor (β = 0.605, p < 0.001). We observed negative relationships between cybrid p-tau217 and cognition and brain morphometry. MCI and AD cybrid proteomes showed mitochondrial dysfunction.

DISCUSSION

mtDNA-determined mitochondrial function affects cell physiology in AD-relevant ways. Our study suggests that mtDNA affects ATN status and clinical state.

Highlights

Mitochondrial DNA (mtDNA)–determined mitochondrial function drives Alzheimer's disease (AD) hallmarks.
Cytoplasmic hybrid outcomes associate with mtDNA-donor clinical measures.
Proteomic analyses indicate mitochondrial dysfunction in AD.

Abstract Image

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线粒体DNA影响衰老和阿尔茨海默病中的tau磷酸化

线粒体功能受损见于阿尔茨海默病（AD），但其作用尚不清楚。线粒体DNA （mtDNA）支持生物能量代谢，但不确定它如何影响阿尔茨海默病的神经病理。方法：我们使用由表达来自认知健康（CH）、轻度认知障碍（MCI）或AD个体的mtDNA的SH-SY5Y细胞制成的细胞系，研究mtDNA决定的线粒体功能对淀粉样蛋白、tau蛋白和神经退行性变（ATN）标志物的影响。杂交测量与认知和脑形态测量相关。结果：与表达CH个体mtDNA的杂合体相比，MCI和AD杂合体含有更多磷酸化的tau-217 （p-tau217）、p-tau181和总tau蛋白。杂种p-tau217与mtDNA供体血浆p-tau217相关(β = 0.605, p <；0.001)。我们观察到p-tau217与认知和脑形态计量学呈负相关。MCI和AD混合蛋白组表现出线粒体功能障碍。mtdna决定的线粒体功能以ad相关的方式影响细胞生理。我们的研究表明mtDNA影响ATN状态和临床状态。线粒体DNA （mtDNA）决定的线粒体功能驱动阿尔茨海默病（AD）的标志。细胞质杂交结果与mtdna供体临床指标相关。蛋白质组学分析表明AD患者存在线粒体功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.