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An antibody to the β-secretase cleavage site on amyloid-β-protein precursor inhibits amyloid-β production

Thomas, Rhian Sara, Liddell, Janet Eryl, Murphy, Lynne Sharon, Pache, David Michael and Kidd, Emma Jane ORCID: 2006. An antibody to the β-secretase cleavage site on amyloid-β-protein precursor inhibits amyloid-β production. Journal of Alzheimer's Disease 10 (4) , pp. 379-390.

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Proteolytic cleavage of amyloid-?-protein precursor (A?PP) by ?- and ?-secretases results in production of the amyloid-? peptide (A?) that accumulates in the brains of sufferers of Alzheimer's disease (AD). We have developed a monoclonal antibody, 2B12, which binds in the vicinity of the ?-secretase cleavage site on A?PP but does not bind within the A? region. We hypothesised that this antibody, directed against the substrate rather than the enzyme, could inhibit cleavage of A?PP by ?-secretase via steric hindrance and thus reduce downstream production of A?. The antibody would enter cells by binding to A?PP when it is at the cell surface and then be internalised with the protein. We subsequently demonstrated that, after addition of 2B12 to standard growth media, this antibody was indeed capable of inhibiting A?40 production in neuroblastoma and astrocytoma cells expressing native A?PP, as measured by an ELISA. This inhibition was both concentration- and time-dependent and was specific to 2B12. We were only able to inhibit approximately 50% of A?40 production suggesting that not all A?PP is trafficked to the cell surface. We propose that this antibody could be used as a novel, putative therapy for the treatment of AD.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: Alzheimer's disease ; Monoclonal antibodies ; Amyloid ? ; ?-secretase ; Amyloid ?-protein precursor ; Steric hindrance
ISSN: 1387-2877
Last Modified: 17 Oct 2022 08:45

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