Open AccessNeuron‐specific deletion of presenilin enhancer2 causes progressive astrogliosis and age‐related neurodegeneration in the cortex independent of the Notch signaling
Author(s) -
Bi HuiRu,
Zhou CuiHua,
Zhang YiZhi,
Cai XuDong,
Ji MuHuo,
Yang JianJun,
Chen GuiQuan,
Hu YiMin
Publication year - 2021
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13454
Subject(s) - astrogliosis , neurodegeneration , presenilin , neuroscience , neuroinflammation , gliosis , conditional gene knockout , notch signaling pathway , biology , alzheimer's disease , medicine , pathology , central nervous system , signal transduction , microbiology and biotechnology , disease , immunology , inflammation , biochemistry , gene , phenotype
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. Methods 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. Results 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. Conclusions 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.