Institut Clinique de la Souris (ICS), Phenomin, Illkirch, France.
Laboratory of Integrative and Systems Physiology (LISP-NCEM), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Brain Res. 2014 Jan 13;1542:32-40. doi: 10.1016/j.brainres.2013.10.003. Epub 2013 Oct 16.
Apolipoprotein E (ApoE) is found in three different forms in humans (ApoE2, ApoE3 and ApoE4), and ApoE polymorphism is recognized as a major risk factor for Alzheimer's disease (AD). ApoE is involved in lipid and cholesterol transport, cell repair, and amyloid-β deposition and certain studies suggest potential implications in neurogenesis. In this regard, we investigated the possible impact of the three different human ApoE isoforms on neurogenesis. We used ApoE knock-in mice of different ages and sex, and quantified newborn cells in the hippocampus by flow cytometry. Young adult ApoE4 mice (10-12 week-old) from both sexes displayed reduced neurogenesis compared with wild-types and the other genotypes. In addition, young adult ApoE2 female mice showed improved hippocampal progenitor cell proliferation. In older mice (1 year), hippocampal neurogenesis was globally decreased, particularly in females, and the difference between ApoE4 and the other genotypes observed in young animals disappeared for the two sexes, except for aged ApoE3 females. Indeed, a surprising protective effect of the ApoE3 genotype was observed in aged females. Our study highlights the role of ApoE in neurogenesis, and shows for the first time an early inequality between the ApoE genotypes. The reduced neurogenesis observed for the ApoE4 genotype and the improved results obtained in young ApoE2 females support the idea of a difference in the balance between neuronal birth and death modulated by the ApoE polymorphism in young animals. The maintenance of this balance and its modulation can influence pathophysiological mechanisms predisposing to neurodegenerative diseases like AD.
载脂蛋白 E（ApoE）在人类中以三种不同形式存在（ApoE2、ApoE3 和 ApoE4），ApoE 多态性被认为是阿尔茨海默病（AD）的主要危险因素。ApoE 参与脂质和胆固醇转运、细胞修复以及淀粉样蛋白-β沉积，某些研究表明其在神经发生中具有潜在的影响。在这方面，我们研究了三种不同的人类 ApoE 同工型对神经发生的可能影响。我们使用了不同年龄和性别的 ApoE 基因敲入小鼠，并通过流式细胞术定量海马中的新生细胞。与野生型和其他基因型相比，年轻成年 ApoE4 小鼠（10-12 周龄）的神经发生减少。此外，年轻成年 ApoE2 雌性小鼠的海马祖细胞增殖得到改善。在老年小鼠（1 岁）中，海马神经发生普遍减少，特别是在雌性中，而在年轻动物中观察到的 ApoE4 与其他基因型之间的差异在两性中均消失，除了老年 ApoE3 雌性小鼠。事实上，在老年雌性中观察到了 ApoE3 基因型的惊人保护作用。我们的研究强调了 ApoE 在神经发生中的作用，并首次显示了 ApoE 基因型之间的早期不平等。ApoE4 基因型观察到的神经发生减少和年轻 ApoE2 雌性获得的改善结果支持了在年轻动物中 ApoE 多态性调节神经元出生和死亡之间平衡的差异的观点。这种平衡的维持和调节可以影响易患神经退行性疾病（如 AD）的病理生理机制。
