Figure 3.

Relative timeline for BACE1 and Aβ evolution. Simplified animal phylogeny with key events supported in this paper and our previous paper [11]. Pre-duplicate BACE1/2 predates animal origins and can be found in extant choanoflagellates, as well as in ctenophores and placozoans (not shown for simplicity). Cnidaria are the most basal group that definitively shows BACE1. We demonstrate that this gene can proteolyze APP/Aβ, while BACE1/2 genes cannot. This proteolytic ability thus correlates with the likely advent of BACE1 by gene duplication. Strikingly, the ability of BACE1 to proteolyze APP/Aβ predates the actual origin of Aβ in vertebrates by several hundred million years.