ATBF1 is a Novel Amyloid-β Protein Precursor (AβPP) Binding Protein that Affects AβPP Expression

Article type: Research Article

Authors: Uhm, Kyung-Ok^{a; 1} | Kim, Mi-Jeong^{a; 1} | Kawaguchi, Makoto^b | Akatsu, Hiroyasu^{c; d} | Miura, Yutaka^e | Misumi, Sachiyo^f | Hida, Hideki^f | Choi, Eun-Kyoung^g | Kim, Yong-Sun^h | Michikawa, Makotoⁱ | Jung, Cha-Gyun^{a; f; *}

Affiliations: [a] Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan | [b] Department of Pathology, Niigata Rosai Hospital, Niigata, Japan | [c] Choju Medical Institute, Fukushimura Hospital, Toyohashi, Japan | [d] Department of Community-based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan | [e] Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan | [f] Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan | [g] Laboratory of Cellular Aging and Neurodegeneration, Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do, Korea | [h] Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Gangwon-do, Korea | [i] Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan

Correspondence: [*] Correspondence to: Cha-Gyun Jung, Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Science, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan. Tel.: +81 52 853 8136; Fax: +81 52 842 3069; E-mail: jung@med.nagoya-cu.ac.jp.

Note: [1] These authors contributed equally to this work.

Abstract: The cytoplasmic C-terminal domain of amyloid-β protein precursor (AβPP) binds to several proteins that regulate the trafficking and processing of AβPP and affects amyloid-β (Aβ) 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 Aβ42 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 AβPP695 increased steady-state levels of AβPP via the binding of ATBF1 to the AβPP cytoplasmic domain (amino acids 666–690), resulting in increased Aβ production and cellular and soluble AβPP (sAβPP) levels without affecting the activity or levels of AβPP processing enzymes (α-, β-, or γ-secretase). Conversely, knockdown of endogenous ATBF1 reduced levels of cellular AβPP, sAβPP, and Aβ in HEK293 cells overexpressing human AβPP695. Our findings provide insight into the dynamics of AβPP processing and Aβ production, and suggest that ATBF1 is a novel AβPP binding protein that may be a suitable therapeutic target for AD.

Keywords: Aβ production, AβPP binding protein, AβPP stabilization, Alzheimer's disease, ATBF1

DOI: 10.3233/JAD-140612

Journal: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 243-257, 2015