Ren_2019_Curr.Alzheimer.Res_16_39

BACKGROUND: beta-amyloid (Abeta) aggregation plays an important role in the pathogenesis of Alzheimer's disease (AD), and astrocytes can significantly inhibit Abeta aggregation. Astrocytic alpha7 Neuronal Nicotinic Acetylcholine Receptor (nAChR) upregulation detected in the AD brains is closely associated with Abeta deposits. However, the relationships between the astrocytic alpha7 nAChRs and Abeta aggregation remain unclear. METHODS: The Abeta oligomers levels in astrocytic cell lysates and culture medium were measured after treatment with nicotine or co-treatment with a Phosphatidylinositol 3-Kinase (PI3K)-protein kinase B (Akt) inhibitor. The level of alphaB-Crystallin (Cryab) in astrocytes treated with nicotine for different times or co-treated with alpha7 nAChR antagonists as well as co-incubated with a PI3K or mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor was determined by western blotting. RESULTS: In this study, nicotine pre-treatment in primary astrocytes markedly inhibited Abeta aggregation and upregulated endogenous astrocytic Cryab, while the nicotine-mediated neuroprotective effect was reversed by pre-treatment with a selective alpha7 nAChR antagonist. Furthermore, this neuroprotection against Abeta aggregation was suppressed by LY294002, a PI3K inhibitor. Pre-treatment with nicotine significantly increased the levels of phosphorylated Akt, an effector of PI3K in astrocytes. CONCLUSION: alpha7 nAChR activation and PI3K/Akt signaling transduction contributed to nicotinemediated neuroprotection against Abeta aggregation by modulating endogenous astrocytic Cryab.