Beta-secretase 1

Beta-secretase 1 (BACE1), also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1, membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an is_associated_with::enzyme that in humans is encoded by the BACE1 is_associated_with::gene.

BACE1 is an aspartic-acid is_associated_with::protease important in the formation of is_associated_with::myelin sheaths in peripheral nerve cells. The is_associated_with::transmembrane protein contains two active site is_associated_with::aspartate residues in its is_associated_with::extracellular is_associated_with::protein domain and may function as a dimer.

Role in Alzheimer's disease


Generation of the 40 or 42 is_associated_with::amino acid-long amyloid-β is_associated_with::peptides that aggregate in the is_associated_with::brain of Alzheimer's patients requires two sequential cleavages of the is_associated_with::amyloid precursor protein (APP). Extracellular cleavage of APP by BACE1 creates a soluble extracellular fragment and a cell membrane-bound fragment referred to as C99. Cleavage of C99 within its transmembrane domain by γ-secretase releases the intracellular domain of APP and produces amyloid-β. Since is_associated_with::alpha-secretase cleaves APP closer to the is_associated_with::cell membrane than BACE1 does, it removes a fragment of the amyloid-β peptide. Initial cleavage of APP by alpha-secretase rather than BACE1 prevents eventual generation of amyloid-β.

Unlike APP and the is_associated_with::presenilin proteins important in γ-secretase, no known is_associated_with::mutations in the is_associated_with::gene encoding BACE1 cause early-onset, is_associated_with::familial Alzheimer's disease, which is a rare form of the disorder. However, levels of this enzyme have been shown to be elevated in the far more common late-onset sporadic Alzheimer's. The physiological purpose of BACE's cleavage of APP and other transmembrane proteins is unknown. is_associated_with::BACE2 is a close homolog of BACE1 with no reported APP cleavage in vivo.

However a single residue mutation in APP reduces the ability of BACE1 to cleave it to produce amyloid-beta and reduces the risk of Alzheimers and other cognitive declines.

BACE inhibitors
Drugs to block this enzyme (BACE inhibitors) in theory would prevent the build up of beta-amyloid and may help slow or stop Alzheimers disease.

Several companies are in the early stages of development and testing of this potential class of treatment. In March 2008 phase I results were reported for CoMentis Inc's candidate CTS-21166.

In April 2012 is_associated_with::Merck & Co., Inc reported phase I results for its candidate is_associated_with::MK-8931. Merck began a Phase II/III trial of MK-8931 in December, 2012 estimated to be completed in July 2019. In September 2014 is_associated_with::AstraZeneca and is_associated_with::Eli Lilly and Company announced an agreement to codevelop is_associated_with::AZD3293. A pivotal Phase II/III clinical trial of is_associated_with::AZD3293 started in late 2014 and is planned to recruit 1,500 patients and end in May 2019.

Tests in mice have indicated that BACE proteases, specifically BACE1, are necessary for the proper function of is_associated_with::muscle spindles. These results raise the possibility that BACE inhibiting drugs currently being investigated for the treatment of Alzheimer's may have significant side effects related to impaired motor coordination, though BACE1 knockout mice are healthy.

Relationship to plasmepsin
BACE1 is distantly related to the pathogenic aspartic-acid protease is_associated_with::plasmepsin, which is a potential target for future anti-malarial drugs.