Regulation of APP phosphorylation

2014 Fiscal Year Final Research Report

• Project/Area Number: 24790260
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Nagasaki University
• Principal Investigator: ASAI Masashi 長崎大学, 医歯薬学総合研究科(薬学系), 助教 (90383223)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: アルツハイマー病 / ダウン症 / APP / リン酸化 / DYRK1A / RCNA1 / ネプリライシン

Outline of Final Research Achievements

To treat Alzheimer's disease, it is required to reduce the amount of amyloid-β peptide in the brain. γ-Secretase prefer phosphorylated C-terminal fragments of precursor protein of amyloid-β peptide (APP) as a substrate. To identify the molecules related with APP phosphorylation, DYRK1A (dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A) and RCAN1 (regulator of calcineurin 1) on chromosome 21 were focused. Overexpression of DYRK1A leaded to APP and tau phosphorylation, while overexpression of RCAN1 leaded to tau phosphorylation, but not APP. Moreover, overexpression of either or both leaded to decrease in the peptidase activity of neprilysin and increase in of the phosphorylation of neprilysin. Treatment of a DYRK1A inhibitor reduced Aβ levels in the medium. These results suggest that DYRK1A and RCAN1A are potential targets of drug development to treatment of Alzheimer's disease.

Free Research Field

生化学