Early Animal Origin of BACE1 APP/Aβ Proteolytic Function.

Area of Science:

• Evolutionary biology
• Neuroscience
• Biochemistry

Background:

• Alzheimer's disease involves beta-amyloid (Aβ) accumulation in the brain.
• Aβ is produced by the proteolysis of amyloid precursor protein (APP) by enzymes like BACE1.
• BACE1 is a rate-limiting enzyme in Aβ production and a therapeutic target.

Purpose of the Study:

• To investigate the evolutionary origin and timing of BACE1's proteolytic function.
• To understand when BACE1 evolved its specific role in APP/Aβ processing.

Main Methods:

• Functional evolutionary approach examining BACE1 orthologs across early animal lineages.
• Testing the APP/Aβ cleaving activity of BACE1 from cnidarians (Hydra).
• Analyzing BACE1/2 genes from ctenophores (Mnemiopsis) and choanoflagellates (Monosiga).

Main Results:

• The most basal BACE1 ortholog was found in cnidarians.
• Cnidarian BACE1 (from Hydra) demonstrated the ability to cleave APP and release Aβ.
• More divergent BACE1/2 genes from ctenophores and choanoflagellates lacked this specific proteolytic activity.
• BACE1 likely evolved from a gene duplication event near the base of the animal clade.

Conclusions:

• The specific proteolytic function of BACE1 evolved during the early diversification of animals.
• This function predates the evolution of its substrate, APP/Aβ, by hundreds of millions of years.
• The origin of BACE1's APP/Aβ cleaving function is traced to the early animal evolutionary period.