Human skeletal muscle mitochondrial pathways are impacted by a neuropathologic diagnosis of Alzheimer's disease

IF 5.1 2区 医学 Q1 NEUROSCIENCES
Chelsea N. Johnson , Mara R. Evans , Anneka E. Blankenship , Casey S. John , Michaella J. Rekowski , Michael P. Washburn , Andy Phan , Cynthia M. Gouvion , Mohammad Haeri , Russell H. Swerdlow , Paige C. Geiger , Jill K. Morris
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Abstract

Alzheimer's disease (AD) is associated with reduced lean mass and impaired skeletal muscle mitochondrial and motor function. Although primary mitochondrial defects in AD may underlie these findings, molecular alterations in AD have not been thoroughly examined in human skeletal muscle. Here, we used two human skeletal muscle types, quadriceps (n = 81) and temporalis (n = 66), to compare the proteome of individuals with a neuropathologic AD diagnosis based on AD Neuropathologic Change (ADNPC+: n = 54 temporalis, 44 quadriceps) to controls (ADNPC-: n = 27 temporalis, 22 quadriceps). We determined the effects of ADNPC status within each muscle and within apolipoprotein E4 (APOE4) carriers and APOE4 non-carriers. Pathways that support mitochondrial metabolism, including oxidative phosphorylation, were downregulated in skeletal muscle of ADNPC+ versus ADNPC- individuals. Similar mitochondrial effects were observed across muscle types and APOE4 carrier groups, but nearly four times as many proteins were altered in temporalis versus quadriceps tissue and mitochondrial effects were most pronounced in APOE4 carriers compared to APOE4 non-carriers. Of all detected oxidative phosphorylation proteins, the expression of ∼29–61 % (dependent on muscle/APOE4 carrier group) significantly correlated with AD progression, ranked by Clinical Dementia Rating and ADNPC scores. Of these, 23 proteins decreased in expression with greater AD progression in all skeletal muscle type and APOE4 carrier groups. This is the first study to assess differences in the human skeletal muscle proteome in the context of AD. Our work shows that systemic mitochondrial alterations in AD extend to skeletal muscle and these effects are amplified by APOE4 and correlate with AD progression.

Abstract Image

人类骨骼肌线粒体通路受到阿尔茨海默病神经病理诊断的影响
阿尔茨海默病(AD)与瘦体重减少和骨骼肌线粒体和运动功能受损有关。尽管阿尔茨海默病的线粒体缺陷可能是这些发现的基础,但阿尔茨海默病的分子改变尚未在人类骨骼肌中得到彻底的研究。在这里,我们使用两种人类骨骼肌类型,股四头肌(n = 81)和颞肌(n = 66),比较基于AD神经病理学改变(ADNPC+: n = 54个颞肌,44个股四头肌)和对照组(ADNPC-: n = 27个颞肌,22个股四头肌)的神经病理学AD诊断个体的蛋白质组。我们确定了ADNPC状态在每块肌肉以及载脂蛋白E4 (APOE4)携带者和APOE4非携带者中的影响。支持线粒体代谢的途径,包括氧化磷酸化,在ADNPC+与ADNPC-个体的骨骼肌中下调。在不同肌肉类型和APOE4携带者组中观察到类似的线粒体效应,但在颞肌和股四头肌组织中,线粒体效应在APOE4携带者中最为明显,而在非APOE4携带者中,线粒体效应几乎是APOE4携带者的四倍。在所有检测到的氧化磷酸化蛋白中,29 - 61%(依赖于肌肉/APOE4携带者组)的表达与AD进展显著相关,根据临床痴呆评分和ADNPC评分进行排名。其中,在所有骨骼肌型和APOE4携带者组中,23种蛋白的表达随着AD的加重而下降。这是第一个评估AD背景下人类骨骼肌蛋白质组差异的研究。我们的研究表明,AD的系统性线粒体改变延伸到骨骼肌,这些影响被APOE4放大,并与AD的进展相关。
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来源期刊
Neurobiology of Disease
Neurobiology of Disease 医学-神经科学
CiteScore
11.20
自引率
3.30%
发文量
270
审稿时长
76 days
期刊介绍: Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.
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