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Specific antibody binding to the APP672-699 region shifts APP processing from ?- to ?-cleavage.

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-? (A?) 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 A?, a variably sized peptide derived from the integral membrane protein amyloid precursor protein (APP). The A? region of APP locates partly within its ecto- and trans-membrane domains. APP is cleaved by three proteases, designated as ?-, ?-, and ?-secretases. Processing by ?- and ?-secretase cleaves the N- and C-terminal ends of the A? region, respectively, releasing A?, whereas ?-secretase cleaves within the A? sequence, releasing soluble APP? (sAPP?). The ?-secretase cleaves at several adjacent sites to yield A? species containing 39-43 amino acid residues. Both ?- and ?-cleavage sites of human wild-type APP are located in APP672-699 region (ectodomain of ?-C-terminal fragment, ED-?-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 (mAbED-C99) blocks human wild-type APP endocytosis and shifts its processing from ?- to ?-cleavage, as evidenced by elevated accumulation of cell surface full-length APP and ?-CTF together with reduced sAPP? and ?-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 ?-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.

SUBMITTER: Li S

PROVIDER: S-EPMC4454311 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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

Li S S Deng J J Hou H H Tian J J Giunta B B Wang Y Y Sawmiller D D Smith A A Sanberg P R PR Obregon D D Mori T T Tan J J

Cell death & disease 20140814

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- an ...[more]

PMID: 25118934

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Dataset Information

Specific antibody binding to the APP672-699 region shifts APP processing from ?- to ?-cleavage.

Publications

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

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