We propose the following evolutionary history. As a consequence of genome duplications during the emergence of chordates, the single Ur-BACE was derived from a cathepsin D/E-like ancestor and evolved distinct sequence properties. After another duplication event the accelerated change in BACE2 suggests neofunctionalisation, perhaps related to its peripheral tissue distribution. This contrasts with the more conserved sequence for BACE1 and preservation of the ancestral, possibly neuronal, Ur-BACE function. In the mammalian lineage Ka/Ks ratios suggest continuing adaptation of the terminal exons but that purifying selection has been maintained in regions associated with catalysis. The branch lengths to the ascidian sequences are generally longer than those in the BACE1 and BACE2 families, which suggests different evolutionary constraints. Related to this is the observation that most of the reported human BACE1 substrates, including APP, seem to be absent in Ciona (results not shown) but have high-scoring matches in the other species.
Our data will facilitate the choice of new functional genomics experiments to illuminate the roles of BACE. Comparisons between knock-outs or knock-downs for the single Ur-BACE, for example against Zebra fish for each and both of the two paralogues, could reveal important undiscovered ancestral functions that the mammalian orthologues may still have. The availability of BACE1-selective and BACE2 cross-reactive inhibitors offers additional experimental options. Given the pressing medical need it is to be hoped that drug candidates entering clinical development for AD will progress. However, advancing our understanding of the evolution of these proteases remains important not only to assess possible consequences of BACE1 inhibition but also what level of BACE1/BACE2 specificity is necessary.
Plaque formation in Alzheimer's Disease (AD) is seeded by excision products of Amyloid precursor protein (APP) generated by the combined...
Plaque formation in Alzheimer's Disease (AD) is seeded by excision products of Amyloid precursor protein (APP) generated by the combined activities of beta and gamma secretases. To reduce the production of these neurotoxic peptides the inhibition of beta-secretase (Beta-site APP Cleaving Enzyme, BACE1, Swiss-Prot P56817) is being intensively pursued as a possible therapy for AD and all drug candidates are screened for selectivity against the paralogue (BACE2, Swiss-Prot Q9Y5Z0) which shares 50% sequence identity.