Hui-Ru Bi1, Cui-Hua Zhou2, Yi-Zhi Zhang1, Xu-Dong Cai1, Mu-Huo Ji3, Jian-Jun Yang3, Gui-Quan Chen1, Yi-Min Hu2. 1. Model Animal Research Center, MOE Key Laboratory of Model Animal for Disease Study, Medical School, Nanjing University, Nanjing, China. 2. Department of Anesthesiology, The Second Affiliated Changzhou People's Hospital of Nanjing Medical University, Changzhou, China. 3. Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract
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.
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.
Authors: A Goate; M C Chartier-Harlin; M Mullan; J Brown; F Crawford; L Fidani; L Giuffra; A Haynes; N Irving; L James Journal: Nature Date: 1991-02-21 Impact factor: 49.962
Authors: Leonidas Chouliaras; Diego Mastroeni; Elaine Delvaux; Andrew Grover; Gunter Kenis; Patrick R Hof; Harry W M Steinbusch; Paul D Coleman; Bart P F Rutten; Daniel L A van den Hove Journal: Neurobiol Aging Date: 2013-04-09 Impact factor: 4.673