Beta-site amyloid precursor protein cleaving enzyme 1 messenger RNA (BACE1 mRNA)

Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) messenger RNA (mRNA) is the transcript that encodes the BACE1 enzyme, also known as beta-secretase. BACE1 is a transmembrane aspartyl protease that performs the rate-limiting step in the proteolytic processing of amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides [1]. The accumulation of Aβ into neurotoxic oligomers and plaques is a central event in the pathogenesis of Alzheimer's disease [2]. By targeting BACE1 mRNA with antisense oligonucleotides (ASOs) or RNA interference (RNAi) molecules, researchers aim to reduce the synthesis of the BACE1 protein, thereby decreasing the production of Aβ [3]. This approach differs from small-molecule inhibition by preventing the enzyme's formation rather than blocking its active site. Clinical development of BACE1-targeted therapies has been complicated by safety concerns, including potential cognitive worsening and off-target effects, as BACE1 also plays roles in myelination and synaptic plasticity [4]. Citations: [1] Vassar R, et al. Science. 1999;286(5440):735-41. [2] Hardy J, Selkoe DJ. Science. 2002;297(5580):353-6. [3] DeVos SL, Miller TM. Neurotherapeutics. 2013;10(3):486-97. [4] Das B, Yan R. Biol Psychiatry. 2019;86(11):813-825.

Other names

Beta-secretase 1 mRNAMemapsin-2 mRNAAspartyl protease 2 mRNABACE mRNAASP2 mRNA

Antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs) bind to the BACE1 mRNA through complementary base pairing, triggering its degradation via RNase H or the RNA-induced silencing complex (RISC), which prevents the translation of the BACE1 enzyme [3, 4].