Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Medical School, Nanjing University, Nanjing, China.
Department of Anesthesiology, The Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, China.
CNS Neurosci Ther. 2021 Feb;27(2):174-185. doi: 10.1111/cns.13454. Epub 2020 Sep 22.
Presenilin enhancer2 (Pen-2) is an essential subunit of γ-secretase, which is a key protease responsible for the cleavage of amyloid precursor protein (APP) and Notch. Mutations on Pen-2 cause familial Alzheimer disease (AD). However, it remains unknown whether Pen-2 regulates neuronal survival and neuroinflammation in the adult brain.
Forebrain neuron-specific Pen-2 conditional knockout (Pen-2 cKO) mice were generated for this study. Pen-2 cKO mice expressing Notch1 intracellular domain (NICD) conditionally in cortical neurons were also generated.
Loss of Pen-2 causes astrogliosis followed by age-dependent cortical atrophy and neuronal loss. Loss of Pen-2 results in microgliosis and enhanced inflammatory responses in the cortex. Expression of NICD in Pen-2 cKO cortices ameliorates neither neurodegeneration nor neuroinflammation.
Pen-2 is required for neuronal survival in the adult cerebral cortex. The Notch signaling may not be involved in neurodegeneration caused by loss of Pen-2.
早老素增强因子 2（Pen-2）是 γ-分泌酶的必需亚基，γ-分泌酶是一种关键的蛋白酶，负责切割淀粉样前体蛋白（APP）和 Notch。Pen-2 上的突变会导致家族性阿尔茨海默病（AD）。然而，目前尚不清楚 Pen-2 是否调节成年大脑中的神经元存活和神经炎症。
本研究生成了大脑前体细胞特异性 Pen-2 条件性敲除（Pen-2 cKO）小鼠。还生成了在皮质神经元中条件性表达 Notch1 细胞内结构域（NICD）的 Pen-2 cKO 小鼠。
Pen-2 的缺失会导致星形胶质细胞增生，随后出现皮质萎缩和神经元丢失。Pen-2 的缺失会导致小胶质细胞增生和皮质炎症反应增强。在 Pen-2 cKO 皮质中表达 NICD 既不能改善神经退行性变也不能改善神经炎症。
Pen-2 是成年大脑皮质中神经元存活所必需的。Notch 信号通路可能不参与 Pen-2 缺失引起的神经退行性变。
