Neuroprotection by aripiprazole against ?-amyloid-induced toxicity by P-CK2? activation via inhibition of GSK-3?.

ABSTRACT: Psychosis is reported over 30% of patients with Alzheimer's disease (AD) in clinics. Aripiprazole is an atypical antipsychotic drug with partial agonist activity at the D2 dopamine and 5-HT1A receptors with low side-effect profile. We identified aripiprazole is able to overcome the amyloid-? (A?)-evoked neurotoxicity and then increase the cell viability. This study elucidated the mechanism(s) by which aripiprazole ameliorates A?1-42-induced decreased neurite outgrowth and viability in neuronal cells. Pretreatment with aripiprazole increased Brain-derived neurotrophic factor (BDNF) mRNA and protein expressions in N2a cells. Additionally, phosphorylated casein kinase 2? at Y 255 (P-CK2?) was increased in time- and concentration-dependent manners. Furthermore, A?1-42-induced decreased BDNF and P-CK2? expression were increased over control level by aripiprazole. Subsequently, A?1-42-induced decreased levels of phosphorylated glycogen synthase-3? at Ser9 (P-GSK-3?) and nuclear P-?-catenin (Ser675) were elevated by aripiprazole, which were inhibited by K252A (inhibitor of BDNF receptor) and tetrabromocinnamic acid (TBCA, CK2 inhibitor), indicating that BDNF and P-CK2? activation are implicated in the aripiprazole effects. Expressions of cyclin D1 and insulin-like growth factor 2 (IGF2) mRNA were increased by aripiprazole; even in the presence of A?1-42, which was blocked by K252A and TBCA. In CK2? gene-silenced N2a cells, aripiprazole failed to increase P-GSK-3? and P-?-catenin expressions. Consequently, aripiprazole ameliorated A?1-42-induced attenuation of neurite elongation in HT22 cells, and this effect was blocked by both TBCA and imatinib. Decreased viability induced by A?1-42 was recovered by aripiprazole. These findings provide evidence supporting that aripiprazole can provide an effective therapeutic strategy against A?-induced neurotoxicity in AD-associated psychosis.

SUBMITTER: Park SY 

PROVIDER: S-EPMC5746390 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature