title: Amyloid β regulates the expression and function of AIP1.
abstract: Apoptosis signal-regulating kinase 1-interacting (ASK1-interacting) protein-1 (AIP1) is a newly identified novel member of the Ras GTPase-activating protein family, which has been implicated in cell growth inhibition and cell apoptosis. However, the effects of AIP1 in Alzheimer's disease (AD) are unknown. In the present study, we found that AIP1 was elevated in the brain of AD Tg2576 mice and Aβ1-42 treated brain cerebral microvascular endothelial cells (CECs). Aβ1-42 treatment induced the interaction of AIP1 and apoptosis signal-regulating kinase 1 (ASK1), which led to dissociation of ASK1 and its inhibitor 14-3-3. Dissociation of ASK1 from 14-3-3 leads to ASK1 activation. Indeed, Aβ1-42 dephosphorylated ASK1 at Ser-967, suggesting that Aβ1-42 increased ASK1 activity. Importantly, disassociation of ASK1 and 14-3-3 induced by Aβ1-42 could be rescued by silence of AIP1. In addition, down-regulation of AIP1 also led to attenuation of the activation of JNK, as well as p53, downstream signaling targets of ASK1. AIP1 silencing attenuated the pro-apoptotic effects of Aβ1-42 on CECs. We propose that AIP1 mediates Aβ induced ASK1 activation by facilitating dissociation of 14-3-3, suggesting a novel mechanism for Aβ-induced apoptosis in CECs.
authors.affiliation: Department of Neurology, The 89th Hospital of People's Liberation Army, 256 Beigong west Street, Weifang, 261045, Shandong Province, China.
authors.forename: Huaiming
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurology, The 89th Hospital of People's Liberation Army, 256 Beigong west Street, Weifang, 261045, Shandong Province, China.
authors.forename: Lijing
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Neurology, The 89th Hospital of People's Liberation Army, 256 Beigong west Street, Weifang, 261045, Shandong Province, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of medicine, Shandong Province Weifang Brain hospital, Weifang, China.
authors.forename: Xixin
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Neurology, The 89th Hospital of People's Liberation Army, 256 Beigong west Street, Weifang, 261045, Shandong Province, China. zddu2008@163.com.
authors.forename: Zhongde
authors.initials: Z
authors.lastname: Du
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D020703:ras GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048948:14-3-3 Proteins; D016229:Amyloid beta-Peptides; C561450:Dab2ip protein, mouse; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; C075222:amyloid beta-protein (1-42); D020703:ras GTPase-Activating Proteins; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D048670:MAP Kinase Kinase 4