Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Cell Stem Cell. 2009 Dec 4;5(6):634-45. doi: 10.1016/j.stem.2009.10.015.
Apolipoprotein (apo) E, a polymorphic protein with three isoforms (apoE2, apoE3, and apoE4), is essential for lipid homeostasis. Carriers of apoE4 are at higher risk for developing Alzheimer's disease. We have investigated adult neurogenesis in mice with knockout (KO) for apoE or with knockin (KI) alleles for human apoE3 or apoE4, and we report that neurogenesis is reduced in both apoE-KO and apoE4-KI mice. In apoE-KO mice, increased BMP signaling promoted glial differentiation at the expense of neurogenesis. In contrast, in apoE4-KI mice, presynaptic GABAergic input-mediated maturation of newborn neurons was diminished. Tau phosphorylation, an Alzheimer's disease characteristic, and levels of neurotoxic apoE fragments were both elevated in apoE4-KI hippocampal neurons concomitant with decreased GABAergic interneuron survival. Potentiating GABAergic signaling restored neuronal maturation and neurogenesis in apoE4-KI mice to normal levels. These findings suggest that GABAergic signaling can be targeted to mitigate the deleterious effects of apoE4 on neurogenesis.
载脂蛋白 E（apoE）是一种具有三种异构体（apoE2、apoE3 和 apoE4）的多态蛋白，对脂质稳态至关重要。apoE4 携带者患阿尔茨海默病的风险更高。我们已经研究了敲除（KO）apoE 或敲入（KI）人 apoE3 或 apoE4 等位基因的小鼠中的成年神经发生，我们报告说 apoE-KO 和 apoE4-KI 小鼠中的神经发生减少。在 apoE-KO 小鼠中，增加的 BMP 信号促进了神经胶质分化，而不是神经发生。相比之下，在 apoE4-KI 小鼠中，新生神经元的 GABA 能传入介导的成熟受损。tau 磷酸化是阿尔茨海默病的特征之一，神经毒性 apoE 片段的水平在 apoE4-KI 海马神经元中升高，同时 GABA 能中间神经元的存活减少。增强 GABA 能信号可以将 apoE4-KI 小鼠的神经元成熟和神经发生恢复到正常水平。这些发现表明，GABA 能信号可以作为靶点，减轻 apoE4 对神经发生的有害影响。
