Asynchronous evolutionary origins of Aβ and BACE1

Area of Science:

• Evolutionary biology
• Neuroscience
• Biochemistry

Background:

• Alzheimer's disease (AD) pathology involves amyloid beta (Aβ) plaques, formed from amyloid precursor protein (APP) cleavage by secretases.
• While γ-secretase is essential, the roles of BACE1 and Aβ remain unclear, as their known functions relate to disease.

Purpose of the Study:

• Investigate the evolutionary origins of BACE1 and Aβ.
• Determine if BACE1 activity predates the evolution of Aβ.

Main Methods:

• Comparative sequence analysis of APP-like proteins and BACE1 across taxa.
• Biochemical assays to test BACE1 activity from basal chordates on human APP.

Main Results:

• APP-like proteins are widespread in animals, but Aβ sequences are limited to gnathostomes.
• The BACE1 enzyme is conserved in basal chordates (e.g., cnidaria), predating Aβ.
• Basal chordate BACE1 can cleave human APP to liberate Aβ.

Conclusions:

• BACE1 activity evolved significantly earlier than Aβ.
• The ancestral function of BACE1 is likely unrelated to Aβ production or Alzheimer's disease.