title: Mitochondrial modulation of store-operated Ca(2+) entry in model cells of Alzheimer's disease.
abstract: Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer's disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca(2+) signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca(2+), which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer's disease.
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Tuo
authors.initials: T
authors.lastname: Ma
authors.forename: Kai
authors.initials: K
authors.lastname: Gong
authors.forename: Yufang
authors.initials: Y
authors.lastname: Yan
authors.forename: Bo
authors.initials: B
authors.lastname: Song
authors.forename: Xiufang
authors.initials: X
authors.lastname: Zhang
authors.forename: Yandao
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*
chemical_list: D002118:Calcium