Specific antibody binding to the APP672-699 region shifts APP processing from α- to β-cleavage
11] Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Neurosciences, Morsani College of Medicine, University of South Florida, Tampa, FL, USA [2] Center for Translational Research of Neurology Diseases, First Affiliated Hospital, Dalian Medical University, Dalian, China.
Cell Death & Disease
|August 15, 2014
Summary
A novel antibody targeting the APP672-699 region in Alzheimer's disease shifts protein processing, increasing amyloid-beta precursor protein (APP) fragments and offering new insights into sporadic AD pathogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles.
- Amyloid precursor protein (APP) processing by secretases influences Aβ production, a key factor in AD pathogenesis.
- The APP672-699 region is critical for APP processing and function.
Purpose of the Study:
- To investigate the role of the APP672-699 region in APP processing and its potential implications for Alzheimer's disease.
- To evaluate the effects of a specific monoclonal antibody (mAbED-C99) targeting the APP672-699 region on APP processing.
Main Methods:
- Utilized a monoclonal antibody (mAbED-C99) targeting the ectodomain of the beta-C-terminal fragment (ED-β-CTF) of APP.
- Assessed APP endocytosis, secretase cleavage activity (α- and β-secretase), and protein fragment accumulation.
- Administered mAbED-C99 to human wild-type APP transgenic mice and analyzed membrane-associated β-CTF levels.
Main Results:
- mAbED-C99 blocked human wild-type APP endocytosis and shifted processing from α- to β-cleavage.
- Elevated accumulation of cell surface full-length APP and β-CTF, with reduced sAPPα and α-CTF levels, was observed.
- mAbED-C99 enhanced APP interactions with cholesterol and increased membrane-associated β-CTF in vivo.
Conclusions:
- The APP672-699 region is critical for human wild-type APP processing.
- Targeting this region with antibodies like mAbED-C99 alters APP processing pathways.
- These findings offer potential new therapeutic strategies for sporadic Alzheimer's disease.
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