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Open Access Research article

Pro-domain removal in ASP-2 and the cleavage of the amyloid precursor are influenced by pH

Christina Sidera, Chibuu Liu and Brian Austen*

Author Affiliations

Neurodegeneration Unit, Dept of Surgery, St George's Hospital Medical School, Cranmer Terrace, London SW 17 ORE, UK

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BMC Biochemistry 2002, 3:25  doi:10.1186/1471-2091-3-25

Published: 31 August 2002



One of the signatures of Alzheimer's disease is the accumulation of aggregated amyloid protein, Aβ, in the brain. Aβ arises from cleavage of the Amyloid Precursor protein by β and γ secretases, which present attractive candidates for therapeutic targeting. Two β-secretase candidates, ASP-1 and ASP-2, were identified as aspartic proteases, both of which cleave the amyloid precursor at the β-site. These are produced as immature transmembrane proteins containing a pro-segment.


ASP-2 expressed in HEK293-cells cleaved the Swedish mutant amyloid precursor at different β-sites at different pHs in vitro. Recent reports show that furin cleaves the pro-peptide of ASP-2, whereas ASP-1 undergoes auto-catalysis. We show that purified recombinant ASP-2 cleaves its own pro-peptide at ph 5 but not pH 8.5 as seen by mass spectrometry, electrophoresis and N-terminal sequencing.


We suggest that ASP-2 processing as well as activity are influenced by pH, and hence the cellular localisation of the protein may have profound effects on the production of Aβ. These factors should be taken into consideration in the design of potential inhibitors for these enzymes.