biostudies-literatureLangeland JANational Science Foundation320https://www.ebi.ac.uk/biostudies/studies/S-EPMC11117577biostudies-literatureUnknown13(5)Alzheimer's disease is characterized, in part, by the accumulation of β-amyloid (Aβ) in the brain. Aβ is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting enzyme in the production of Aβ, and a target for therapeutics, it is of interest to know when its proteolytic function evolved and for what purpose. Here, we take a functional evolutionary approach to show that BACE1 likely evolved from a gene duplication event near the base of the animal clade and that BACE1 APP/Aβ proteolytic function evolved during early animal diversification, hundreds of millions of years before the evolution of the APP/Aβ substrate. Our examination of BACE1 APP/Aβ proteolytic function includes cnidarians, ctenophores, and choanoflagellates. The most basal BACE1 ortholog BiologyEarly Animal Origin of BACE1 APP/Aβ Proteolytic Function.PMC11117577RUI 1817867Langeland JAMoore DBDeYoung EMVarella RAAguirre AMwenda NBaumann LfalseEarly Animal Origin of BACE1 APP/Aβ Proteolytic Function.Alzheimer's disease is characterized, in part, by the accumulation of β-amyloid (Aβ) in the brain. Aβ is produced via the proteolysis of APP by BACE1 and γ-secretase. Since BACE1 is the rate-limiting enzyme in the production of Aβ, and a target for therapeutics, it is of interest to know when its proteolytic function evolved and for what purpose. Here, we take a functional evolutionary approach to show that BACE1 likely evolved from a gene duplication event near the base of the animal clade and that BACE1 APP/Aβ proteolytic function evolved during early animal diversification, hundreds of millions of years before the evolution of the APP/Aβ substrate. Our examination of BACE1 APP/Aβ proteolytic function includes cnidarians, ctenophores, and choanoflagellates. The most basal BACE1 ortholog 2024-01-01T00:00:00Z2024 May2026-05-20T03:18:23.172Z2026-05-20T03:08:09.306ZS-EPMC111175773878580210.3390/biology13050320