Budny Vanessa, Ruminot Iván, Wybitul Maha, Treyer Valerie, Barros L Felipe, Tackenberg Christian
Institute for Regenerative Medicine, University of Zurich, Schlieren, Switzerland.
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
Transl Psychiatry. 2025 Aug 25;15(1):316. doi: 10.1038/s41398-025-03550-w.
The human brain has high energy demands and tightly regulated mechanisms ensure its activity-dependent energy supply. Glucose hypometabolism is associated with brain aging and has also been linked to neurodegenerative diseases such as Alzheimer's disease (AD). The apolipoprotein E4 (APOE4) allele is the strongest genetic risk factor for AD while APOE2 reduces the risk and APOE3 has been referred to as risk neutral allele. APOE is a major lipid carrier in the brain and is not only involved in the build-up of the two AD hallmark pathologies, β-amyloid (Aβ) plaques and neurofibrillary tangles, but also in several other (patho-)physiological processes including immune response, neuronal growth, synaptic plasticity and energy metabolism. Although there has been recent progress in understanding APOE biology, the exact mechanisms of how APOE (especially APOE4) affects brain energy metabolism are still largely unclear. This review highlights the recent evidence of how APOE isoforms differentially affect the bioenergetic homeostasis of the brain, thereby affecting AD etiology and pathophysiology, and identifies critical questions and emerging topics that require further investigation.
人类大脑对能量需求很高，严格调控的机制确保其依赖活动的能量供应。葡萄糖代谢减退与大脑衰老相关，也与诸如阿尔茨海默病（AD）等神经退行性疾病有关。载脂蛋白E4（APOE4）等位基因是AD最强的遗传风险因素，而APOE2降低风险，APOE3被称为风险中性等位基因。APOE是大脑中的主要脂质载体，不仅参与AD两个标志性病理特征即β-淀粉样蛋白（Aβ）斑块和神经原纤维缠结的形成，还参与包括免疫反应、神经元生长、突触可塑性和能量代谢在内的其他几个（病理-）生理过程。尽管最近在理解APOE生物学方面取得了进展，但APOE（尤其是APOE4）如何影响大脑能量代谢的确切机制仍大多不清楚。本综述强调了APOE异构体如何不同地影响大脑生物能量稳态从而影响AD病因和病理生理学的最新证据，并确定了需要进一步研究的关键问题和新出现的主题。
