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

被引:46
作者
Kim, Byeong Mo [1 ,2 ]
You, Mi-Hyeon [1 ]
Chen, Chun-Hau [3 ]
Suh, Jaehong [4 ]
Tanzi, Rudolph E. [4 ]
Lee, Tae Ho [1 ]
机构
[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Gerontol, Boston, MA 02215 USA
[2] Yonsei Univ, Coll Med, Severance Integrat Res Inst Cerebral & Cardiovasc, Seoul 120752, South Korea
[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Med, Div Hematol Oncol, Boston, MA 02215 USA
[4] Harvard Med Sch, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat Dis, Genet & Aging Res Unit,Dept Neurol, Boston, MA 02129 USA
关键词
A-BETA PEPTIDES; ALZHEIMERS-DISEASE; DAP-KINASE; NEURONAL DIFFERENTIATION; TRANSGENIC MICE; ISOMERASE PIN1; CELL-DEATH; SECRETASE CLEAVAGE; CYTOPLASMIC DOMAIN; OXIDATIVE STRESS;
D O I
10.1093/hmg/ddw114
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Extracellular deposition of amyloid-beta (A beta) peptide, a metabolite of sequential cleavage of amyloid precursor protein (APP), is a critical step in the pathogenesis of Alzheimer's disease (AD). While death-associated protein kinase 1 (DAPK1) is highly expressed in AD brains and its genetic variants are linked to AD risk, little is known about the impact of DAPK1 on APP metabolism and A beta generation. In this study, we demonstrated a novel effect of DAPK1 in the regulation of APP processing using cell culture and mouse models. DAPK1, but not its kinase deficient mutant (K42A), significantly increased human A beta secretion in neuronal cell culture models. Moreover, knockdown of DAPK1 expression or inhibition of DAPK1 catalytic activity significantly decreased A beta secretion. Furthermore, DAPK1, but not K42A, triggered Thr668 phosphorylation of APP, which may initiate and facilitate amyloidogenic APP processing leading to the generation of A beta. In Tg2576 APPswe-overexpressing mice, knockout of DAPK1 shifted APP processing toward non-amyloidogenic pathway and decreased A beta generation. Finally, in AD brains, elevated DAPK1 levels showed co-relation with the increase of APP phosphorylation. Combined together, these results suggest that DAPK1 promotes the phosphorylation and amyloidogenic processing of APP, and that may serve a potential therapeutic target for AD.
引用
收藏
页码:2498 / 2513
页数:16
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