Beta-site APP-cleaving enzyme 2 mRNA (BACE2 mRNA)

Beta-site APP-cleaving enzyme 2 (BACE2) is a transmembrane aspartic protease and a close homolog of BACE1, the primary enzyme involved in the generation of amyloid-beta (Abeta) peptides in Alzheimer's disease (UniProt P56818). Unlike BACE1, BACE2 is predominantly expressed in peripheral tissues such as the pancreas and pigment cells, and it typically functions as a 'theta-secretase' that cleaves the amyloid precursor protein (APP) within the Abeta domain, thereby preventing the formation of toxic Abeta species (PubMed: 36463454). BACE2 also plays a critical role in the shedding of Tmem27 in pancreatic beta cells and the processing of PMEL in melanocytes, making it a therapeutic target for Type 2 Diabetes and a potential anti-target in Alzheimer's drug development (PubMed: 21907142, PubMed: 23754390). Targeting BACE2 mRNA via antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) offers a method to modulate its expression levels, which is being explored to increase beta-cell mass and improve insulin secretion (Esterhazy et al., 2011). However, inhibition of BACE2 is associated with safety concerns such as skin and hair hypopigmentation due to its role in melanosome biogenesis (PubMed: 1.5.3).

Other names

AEPLCALP56ASP1ASP21Asp 1Memapsin-1Theta-secretaseDown region aspartic protease

Small molecule inhibitors bind to the aspartic protease active site of the BACE2 protein to block its catalytic activity (PubMed: 39948713). RNA-based therapeutics, such as siRNAs and antisense oligonucleotides (ASOs), target the BACE2 mRNA transcript to induce its degradation or inhibit translation, thereby reducing the overall levels of the BACE2 enzyme (Esterhazy et al., 2011).