BACE1 encodes a transmembrane aspartyl protease responsible for β-secretase processing of the amyloid precursor protein (APP). APP cleavage by BACE1 is the rate-limiting step in the generation of Aβ peptides, creating the C99 fragment that becomes a substrate for subsequent γ-secretase cleavage. BACE1 is active in the acidic environment of early endosomes and trans-Golgi compartments, where Aβ is generated.

Its role in Aβ generation has made BACE1 a target for therapy development, and rational drug design efforts accelerated when the crystal structure of BACE was solved. A handful of BACE inhibitors have come to clinical trial, though some failed in Phase 1 due to safety concerns. BACE inhibitors are being watched for potential off-target effects of BACE1 inhibition, as the protease cleaves several dozen substrates. The best-studied is the cell surface protein neuregulin 1, whose soluble cleavage product signals through the receptor Erb4 on glial cells to regulate myelination. In addition, BACE1 is known to play a role in neurite outgrowth and muscle spindle formation. BACE knockout mice have mild schizophrenia-like and cognitive phenotypes.

The physiological function of APP processing by BACE1 remains unclear. The homolog BACE2 differs from BACE1 in its expression pattern and substrate specificity, and appears not to contribute significantly to Aβ generation.

References

Other Citations

1. amyloid precursor protein (APP)

Further Reading