Presenilin 1 promotes trypsin-induced neuroprotection via the PAR2/ERK signaling pathway. Effects of presenilin 1 FAD mutations

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• 作者：Angeliki M. Nikolakopoulou^a ; ^b ; ^{nikolako@med.usc.edu" class="auth_mail" title="E-mail the corresponding author} ; Anastasios Georgakopoulos^a ; ^b ; Nikolaos K. Robakis^a ; ^b ; ^{Nikos.robakis@mssm.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Familial Alzheimer's disease ; Presenilin 1 ; Neurotoxicity ; Neuroprotection ; Proteinase-activated receptor 2
• 刊名：Neurobiology of Aging
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：42
• 期：Complete
• 页码：41-49
• 全文大小：1578 K

文摘

Mutants of presenilin 1 (PS1) increase neuronal cell death causing autosomal-dominant familial Alzheimer's disease (FAD). Recent literature shows that treatment of neuronal cultures with low concentrations of trypsin, a member of the serine family of proteases, protects neurons from toxic insults by binding to the proteinase-activated receptor 2 and stimulating survival kinase extracellular signal–regulated kinase (ERK 1/2). Other studies show that PS1 is necessary for the neuroprotective activity of specific neurotrophic factors, such as brain-derived neurotrophic factor, against excitotoxicity and oxidative stress. Here, we show that treatment of mouse cortical neuronal cultures with trypsin activates ERK1/2 and protects neurons against glutamate excitoxicity. The trypsin-dependent ERK activation and neuroprotection requires both alleles of PS1 because neither PS1 knockout nor PS1 hemizygous neuronal cultures can use exogenous trypsin to activate ERK1/2 or increase neuronal survival. The protective effect of PS1 does not depend on its γ-secretase activity because inhibitors of γ-secretase have no effect on trypsin-mediated neuroprotection. Importantly, cortical neuronal cultures either heterozygous or homozygous for PS1 FAD mutants are unable to use trypsin to activate ERK1/2 and rescue neurons from excitotoxicity, indicating that FAD mutants inhibit trypsin-dependent neuroprotection in an autosomal-dominant manner. Furthermore, our data support the theory that PS FAD mutants increase neurodegeneration by inhibiting the ability of neurons to use cellular factors as protective agents against toxic insults.