ATBF1 is a Novel Amyloid-beta Protein Precursor (A beta PP) Binding Protein that Affects A beta PP Expression

作者：Uhm Kyung Ok; Kim Mi Jeong; Kawaguchi Makoto; Akatsu Hiroyasu; Miura Yutaka; Misumi Sachiyo; Hida Hideki; Choi Eun Kyoung; Kim Yong Sun; Michikawa Makoto; Jung Cha Gyun^*

来源：Journal of Alzheimer's Disease, 2015, 43(1): 243-257.

DOI：10.3233/JAD-140612

• A beta production
• A beta PP binding protein
• A beta PP stabilization
• Alzheimer's disease
• ATBF1

The cytoplasmic C-terminal domain of amyloid-beta protein precursor (A beta PP) binds to several proteins that regulate the trafficking and processing of A beta PP and affects amyloid-beta (A beta) production. We previously reported that levels of AT-motif binding factor 1 (ATBF1) are increased in the brains of 17-month-old Tg2576 mice compared with wild-type controls, and that A beta(42) increases ATBF1 expression, inducing death in primary rat cortical neurons. Here, we show that ATBF1 levels are increased in the cytoplasm of hippocampal neurons in Alzheimer's disease (AD) brains compared with non-AD brains. Furthermore, cotransfection of human embryonic kidney (HEK293T) and human neuroblastoma (SH-SY5Y) cells with ATBF1 and A beta PP695 increased steady-state levels of A beta PP via the binding of ATBF1 to the A beta PP cytoplasmic domain (amino acids 666-690), resulting in increased A beta production and cellular and soluble A beta PP (sA beta PP) levels without affecting the activity or levels of A beta PP processing enzymes (alpha-, beta-, or gamma-secretase). Conversely, knockdown of endogenous ATBF1 reduced levels of cellular A beta PP, sA beta PP, and A beta in HEK293 cells overexpressing human A beta PP695. Our findings provide insight into the dynamics of A beta PP processing and A beta production, and suggest that ATBF1 is a novel A beta PP binding protein that may be a suitable therapeutic target for AD.

• 出版日期2015