Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
Kansas University Alzheimer's Disease Center, University of Kansas Medical Center, Kansas City, KS, USA.
J Alzheimers Dis. 2023;92(3):1027-1035. doi: 10.3233/JAD-221192.
Individuals with mild cognitive impairment (MCI) have reduced lipid-stimulated mitochondrial respiration in skeletal muscle. A major risk factor for Alzheimer's disease (AD), the apolipoprotein E4 (APOE4) allele, is implicated in lipid metabolism and is associated with metabolic and oxidative stress that can result from dysfunctional mitochondria. Heat shock protein 72 (Hsp72) is protective against these stressors and is elevated in the AD brain.
Our goal was to characterize skeletal muscle ApoE and Hsp72 protein expression in APOE4 carriers in relationship to cognitive status, muscle mitochondrial respiration and AD biomarkers.
We analyzed previously collected skeletal muscle tissue from 24 APOE4 carriers (60y+) who were cognitively healthy (CH, n = 9) or MCI (n = 15). We measured ApoE and Hsp72 protein levels in muscle and phosphorylated tau181 (pTau181) levels in plasma, and leveraged previously collected data on APOE genotype, mitochondrial respiration during lipid oxidation, and VO2 max.
Muscle ApoE (p = 0.013) and plasma pTau181 levels (p < 0.001) were higher in MCI APOE4 carriers. Muscle ApoE positively correlated with plasma pTau181 in all APOE4 carriers (R2 = 0.338, p = 0.003). Hsp72 expression negatively correlated with ADP (R2 = 0.775, p = <0.001) and succinate-stimulated respiration (R2 = 0.405, p = 0.003) in skeletal muscle of MCI APOE4 carriers. Plasma pTau181 negatively tracked with VO2 max in all APOE4 carriers (R2 = 0.389, p = 0.003). Analyses were controlled for age.
This work supports a relationship between cellular stress in skeletal muscle and cognitive status in APOE4 carriers.
轻度认知障碍（MCI）个体的骨骼肌中脂质刺激的线粒体呼吸减少。载脂蛋白 E4（APOE4）等位基因是阿尔茨海默病（AD）的主要危险因素，与脂代谢有关，并与线粒体功能障碍引起的代谢和氧化应激有关。热休克蛋白 72（Hsp72）对这些应激源具有保护作用，并且在 AD 大脑中升高。
我们的目标是研究 APOE4 携带者骨骼肌中的 ApoE 和 Hsp72 蛋白表达与认知状态、肌肉线粒体呼吸和 AD 生物标志物的关系。
我们分析了 24 名 APOE4 携带者（60 岁以上）的骨骼肌组织，这些携带者认知健康（CH，n=9）或 MCI（n=15）。我们测量了肌肉中的 ApoE 和 Hsp72 蛋白水平以及血浆中的磷酸化 tau181（pTau181）水平，并利用先前收集的 APOE 基因型、脂质氧化过程中的线粒体呼吸和最大摄氧量数据。
MCI APOE4 携带者的肌肉 ApoE（p=0.013）和血浆 pTau181 水平（p<0.001）更高。在所有 APOE4 携带者中，肌肉 ApoE 与血浆 pTau181 呈正相关（R2=0.338，p=0.003）。MCI APOE4 携带者的骨骼肌中，Hsp72 表达与 ADP（R2=0.775，p<0.001）和琥珀酸刺激的呼吸（R2=0.405，p=0.003）呈负相关。在所有 APOE4 携带者中，血浆 pTau181 与 VO2 max 呈负相关（R2=0.389，p=0.003）。分析时控制了年龄。
这项工作支持 APOE4 携带者的骨骼肌细胞应激与认知状态之间的关系。
