Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Department of Psychiatry and Behavioral Neurobiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Genes (Basel). 2024 Oct 25;15(11):1376. doi: 10.3390/genes15111376.
Apolipoprotein E (ApoE) is the leading genetic risk factor for late-onset Alzheimer's disease (AD), which is the leading cause of dementia worldwide. Most people have two ApoE-ε3 (ApoE3) alleles, while ApoE-ε2 (ApoE2) is protective from AD, and ApoE-ε4 (ApoE4) confers AD risk. How these alleles modulate AD risk is not clearly defined, and ApoE's role in lipid metabolism is also not fully known. Lipid droplets increase in AD. However, how ApoE contributes to lipid accumulation in the brain remains unknown. Here, we use to study the effects of ApoE alleles on lipid accumulation in the brain and muscle in a cell-autonomous and non-cell-autonomous manner. We report that pan-neuronal expression of each ApoE allele induces lipid accumulation specifically in the brain, but not in the muscle. However, this was not the case when expressed with muscle-specific drivers. ApoE2- and ApoE3-induced lipid accumulation is dependent on the expression of Dgat2, a key regulator of triacylglycerol production, while ApoE4 still induces lipid accumulation even with knock-down of Dgat2. Additionally, we find that implementation of time-restricted feeding (TRF), a dietary intervention in which food access only occurs in the active period (day), prevents ApoE-induced lipid accumulation in the brain of flies and modulates lipid metabolism genes. Altogether, our results demonstrate that ApoE induces lipid accumulation in the brain, that ApoE4 is unique in causing lipid accumulation independent of Dgat2, and that TRF prevents ApoE-induced lipid accumulation. These results support the idea that lipid metabolism is critical in AD, and that TRF could be a promising therapeutic approach to prevent ApoE-associated dysfunction in lipid metabolism.
载脂蛋白 E (ApoE) 是导致晚发性阿尔茨海默病 (AD) 的主要遗传风险因素，AD 是全球范围内导致痴呆的主要原因。大多数人有两个载脂蛋白 E-ε3 (ApoE3) 等位基因，而载脂蛋白 E-ε2 (ApoE2) 可预防 AD，载脂蛋白 E-ε4 (ApoE4) 则增加 AD 风险。这些等位基因如何调节 AD 风险尚不清楚，载脂蛋白 E 在脂质代谢中的作用也不完全清楚。脂滴在 AD 中增加。然而，载脂蛋白 E 如何导致大脑中的脂质积累仍然未知。 在这里，我们使用 来研究载脂蛋白 E 等位基因在细胞自主和非细胞自主方式下对大脑和肌肉中脂质积累的影响。 我们报告说，每个载脂蛋白 E 等位基因的全神经元表达特异性地诱导大脑中的脂质积累，但不会在肌肉中诱导。然而，当用肌肉特异性驱动子表达时则不是这样。ApoE2 和 ApoE3 诱导的脂质积累依赖于三酰甘油生成的关键调节因子 Dgat2 的表达，而即使敲低 Dgat2，ApoE4 仍诱导脂质积累。此外，我们发现，限时喂养 (TRF) 的实施，即只有在活动期（白天）才能进食的饮食干预，可以防止载脂蛋白 E 诱导的果蝇大脑中的脂质积累，并调节脂质代谢基因。 总之，我们的结果表明，载脂蛋白 E 诱导大脑中的脂质积累，ApoE4 是独特的，可独立于 Dgat2 引起脂质积累，而限时喂养可防止载脂蛋白 E 诱导的脂质积累。这些结果支持这样一种观点，即脂质代谢在 AD 中至关重要，限时喂养可能是预防载脂蛋白 E 相关脂质代谢功能障碍的一种有前途的治疗方法。
