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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
Published on: August 28, 2012
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ATBF1 is a novel amyloid-β protein precursor (AβPP) binding protein that affects AβPP expression
Kyung-Ok Uhm1, Mi-Jeong Kim1, Makoto Kawaguchi2
1Department of Alzheimer's Disease Research, Research Institute, National Center for Geriatrics and Gerontology (NCGG), Morioka, Obu, Aichi, Japan.
Journal of Alzheimer'S Disease : JAD
|August 1, 2014
Summary
AT-motif binding factor 1 (ATBF1) is elevated in Alzheimer's disease (AD) brains and increases amyloid-β precursor protein (AβPP) levels, leading to higher amyloid-β (Aβ) production. Reducing ATBF1 lowers AβPP and Aβ, suggesting ATBF1 as a therapeutic target for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Amyloid-β protein precursor (AβPP) processing and amyloid-β (Aβ) production are central to Alzheimer's disease (AD) pathogenesis.
- The cytoplasmic C-terminal domain of AβPP interacts with regulatory proteins, influencing Aβ production.
- Previous studies indicated elevated AT-motif binding factor 1 (ATBF1) in aged mouse brains and its role in neuronal death.
Purpose of the Study:
- To investigate the role of ATBF1 in Alzheimer's disease (AD) brain pathology.
- To determine if ATBF1 directly interacts with AβPP and affects Aβ production.
- To explore ATBF1 as a potential therapeutic target for AD.
Main Methods:
- Immunohistochemistry on human brain samples to assess ATBF1 levels in AD patients.
- Cell-based assays (HEK293T, SH-SY5Y) involving co-transfection with ATBF1 and AβPP695.
- Western blotting to quantify AβPP, soluble AβPP (sAβPP), and Aβ levels.
- ATBF1 knockdown experiments using siRNA in AβPP-overexpressing cells.
Main Results:
- ATBF1 levels were significantly increased in the cytoplasm of hippocampal neurons in Alzheimer's disease (AD) brains compared to non-AD controls.
- Overexpression of ATBF1 with AβPP695 in HEK293T and SH-SY5Y cells increased steady-state AβPP levels by direct binding to the AβPP cytoplasmic domain (amino acids 666-690).
- This interaction led to elevated Aβ production and increased cellular and soluble AβPP (sAβPP) levels, without altering secretase activity.
- Knockdown of endogenous ATBF1 in AβPP-overexpressing HEK293 cells reduced cellular AβPP, sAβPP, and Aβ levels.
Conclusions:
- ATBF1 is upregulated in the cytoplasm of neurons in Alzheimer's disease (AD) brains.
- ATBF1 directly binds to the cytoplasmic C-terminal domain of AβPP, enhancing AβPP levels and subsequently increasing Aβ production.
- ATBF1 represents a novel AβPP binding protein and a potential therapeutic target for Alzheimer's disease (AD).
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