Alzheimer's beta secretases: pathology, pharmacology and evolution at the dawn of the nervous system
Abstract
This is an updated version of a presentation at Edinburgh University in June with some editing and additional slides on BindingDB patent curation Presented at the Scaggs School of Pharmacy, University of California San Diego, August 28th 2026 as guest of Prof. Michael Gilson Abstract The beta amyloid (APP) cleaving enzyme (BACE1) was identified as a drug target for Alzheimer\'s Disease (AD) in 1999 while its paralog (BACE2) was proposed as a target for type II diabetes (T2DM) in 2011. The generation of BACE1 inhibitors over ~ 25 years has made it one of the most intensely persued AD drug targets, with lead compounds curated by the Guide to Pharmacoly, liteature inhibitors by ChEMBL and compounds from patents by BindingDB. Unfortunately, no less than six small-molecule BACE1 inhibitors have failed in Phase II or III clinical trials for AD. Despite reducing Aβ production, several programs reported cognitive and neuropsychiatric problems, raising questions on the “normal” roles of BACE1. To shed some light on these an evolutionary analysis was undertaken in 2013 (PMID: 24381583). This identified single-copy homologs (UrBACE) wirh 35-45% protein sequence identity to mammalian BACE1 in many basal animal phyla. More homologues have recently been identified from new molluscan genomes, thereby extending support for an evolutionary histroy as a duplication of the UrBACE in fish giving rise to BACE1 and BACE2 paralogues in all vertebrate lineages. In addition, Alpha fold structures for the Sea Urchin UrBACE have been generated. However, it remains unclear what functional roles this enzyme had both before and during evolution of the ancestral nervous system over ~ 800 million years ago. By illuminating UrBACE roles, functional genomics experiments may shed on the clinical failure of human BACE1 inhibitors in AD.
