Inhibition of death-associated protein kinase 1 attenuates the phosphorylation and amyloidogenic processing of amyloid precursor protein

摘要: Extracellular deposition of amyloid-beta (Aβ) peptide, a metabolite sequential cleavage amyloid precursor protein (APP), is critical step in the pathogenesis Alzheimer's disease (AD). While death-associated kinase 1 (DAPK1) highly expressed AD brains and its genetic variants are linked to risk, little known about impact DAPK1 on APP metabolism Aβ generation. In this study, we demonstrated novel effect regulation processing using cell culture mouse models. DAPK1, but not deficient mutant (K42A), significantly increased human secretion neuronal Moreover, knockdown expression or inhibition catalytic activity decreased secretion. Furthermore, K42A, triggered Thr668 phosphorylation APP, which may initiate facilitate amyloidogenic leading generation Aβ. Tg2576 APPswe-overexpressing mice, knockout shifted toward non-amyloidogenic pathway Finally, brains, elevated levels showed co-relation with increase phosphorylation. Combined together, these results suggest that promotes serve potential therapeutic target for AD.