Specific antibody binding to the APP672-699 region shifts APP processing from α- To β-cleavage

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Abstract

Alzheimer's disease (AD), a progressive neurodegenerative disorder that is the most common cause of dementia in the elderly, is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, as well as a progressive loss of synapses and neurons in the brain. The major pertinacious component of amyloid plaques is Aβ, a variably sized peptide derived from the integral membrane protein amyloid precursor protein (APP). The Aβ region of APP locates partly within its ecto- and trans-membrane domains. APP is cleaved by three proteases, designated as α-, β-, and γ-secretases. Processing by β- and γ-secretase cleaves the N- and C-terminal ends of the Aβ region, respectively, releasing Aβ, whereas α-secretase cleaves within the Aβ sequence, releasing soluble APPα (sAPPα). The γ-secretase cleaves at several adjacent sites to yield Aβ species containing 39-43 amino acid residues. Both α- and β-cleavage sites of human wild-type APP are located in APP672-699 region (ectodomain of β-C-terminal fragment, ED-β-CTF or ED-C99). Therefore, the amino acid residues within or near this region are definitely pivotal for human wild-type APP function and processing. Here, we report that one ED-C99-specific monoclonal antibody (mAb ED-C99) blocks human wild-type APP endocytosis and shifts its processing from α- to β-cleavage, as evidenced by elevated accumulation of cell surface full-length APP and β-CTF together with reduced sAPPα and α-CTF levels. Moreover, mAbED-C99 enhances the interactions of APP with cholesterol. Consistently, intracerebroventricular injection of mAbED-C99 to human wild-type APP transgenic mice markedly increases membrane-associated β-CTF. All these findings suggest that APP672-699 region is critical for human wild-type APP processing and may provide new clues for the pathogenesis of sporadic AD. © 2014 Macmillan Publishers Limited All rights reserved.

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Li, S., Deng, J., Hou, H., Tian, J., Giunta, B., Wang, Y., … Tan, J. (2014). Specific antibody binding to the APP672-699 region shifts APP processing from α- To β-cleavage. Cell Death and Disease, 5(8). https://doi.org/10.1038/cddis.2014.336

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