Development of Neoepitope Antibodies Against the β-Secretase Cleavage Site in the Amyloid Precursor Protein

: A detailed understanding of the biochemical events leading to the proteolytic excision of the β-amyloid peptide (A β) from the amyloid precursor protein (APP) has eluded many researchers. This is largely because the measurement of the various APP processing products is technically challenging owing to their low levels of production in in vitro and in vivo test systems. Sequence analysis of products in cell cultures, cerebrospinal fluid (CSF), and amyloid plaques has been used to predict the major cleavage sites resulting from the β- and γ-secretase proteolytic activities that release the Aβ peptide from APP (1 -3). More routine identification of the secretase activities has relied on the specificity and sensitivity of antibodies raised to the predicted cleavage products and has been impeded by the difficulties associated with the generation of such reagents.