Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 10117, Germany.
Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin 13353, Germany.
Aging (Albany NY). 2021 Apr 16;13(8):10891-10919. doi: 10.18632/aging.202978.
Alzheimer's disease (AD) is frequently accompanied by progressing weight loss, correlating with mortality. Counter-intuitively, weight loss in old age might predict AD onset but obesity in midlife increases AD risk. Furthermore, AD is associated with diabetes-like alterations in glucose metabolism. Here, we investigated metabolic features of amyloid precursor protein overexpressing APP23 female mice modeling AD upon long-term challenge with high-sucrose (HSD) or high-fat diet (HFD). Compared to wild type littermates (WT), APP23 females were less prone to mild HSD-induced and considerable HFD-induced glucose tolerance deterioration, despite unaltered glucose tolerance during normal-control diet. Indirect calorimetry revealed increased energy expenditure and hyperactivity in APP23 females. Dietary interventions, especially HFD, had weaker effects on lean and fat mass gain, steatosis and adipocyte hypertrophy of APP23 than WT mice, as shown by H-magnetic-resonance-spectroscopy, histological and biochemical analyses. Proteome analysis revealed differentially regulated expression of mitochondrial proteins in APP23 livers and brains. In conclusion, hyperactivity, increased metabolic rate, and global mitochondrial dysfunction potentially add up to the development of AD-related body weight changes in APP23 females, becoming especially evident during diet-induced metabolic challenge. These findings emphasize the importance of translating this metabolic phenotyping into human research to decode the metabolic component in AD pathogenesis.
阿尔茨海默病（AD）常伴有进行性体重减轻，与死亡率相关。与直觉相反，老年时的体重减轻可能预示着 AD 的发病，但中年时的肥胖会增加 AD 的风险。此外，AD 与葡萄糖代谢的类似糖尿病的改变有关。在这里，我们研究了在长期接受高蔗糖（HSD）或高脂肪饮食（HFD）挑战后，过表达淀粉样前体蛋白的 APP23 雌性小鼠模型中 AD 的代谢特征。与野生型同窝仔（WT）相比，尽管在正常对照饮食期间葡萄糖耐量没有改变，但 APP23 雌性小鼠对轻度 HSD 诱导和相当大的 HFD 诱导的葡萄糖耐量恶化的易感性较低。间接量热法显示 APP23 雌性小鼠的能量消耗增加和活动过度。膳食干预，特别是 HFD，对 APP23 小鼠的瘦体重和脂肪量增加、脂肪变性和脂肪细胞肥大的影响比 WT 小鼠弱，这通过 H-磁共振波谱、组织学和生化分析得到证实。蛋白质组分析显示 APP23 肝脏和大脑中存在线粒体蛋白表达的差异调节。总之，活动过度、代谢率增加和全局线粒体功能障碍可能导致 APP23 雌性小鼠体重变化与 AD 相关，在饮食诱导的代谢挑战期间尤其明显。这些发现强调了将这种代谢表型转化为人类研究的重要性，以破译 AD 发病机制中的代谢成分。
