Neuron‐specific deletion of presenilin enhancer2 causes progressive astrogliosis and age‐related neurodegeneration in the cortex independent of the Notch signaling

INTRODUCTION: 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.