New Enzyme Identified to Fight Alzheimer’s Disease

A newly discovered enzyme could soon become an important new weapon in the fight against Alzheimer’s disease (AD). The enzyme--known as BACE2 (beta-site APP cleaving enzyme 2)--destroys beta-amyloid, a toxic protein fragment that clutters the brains of patients who have the disease.

The study’s findings were published online September 17, 2012, in the journal Molecular Neurodegeneration. The research team, led by Malcolm A. Leissring, PhD, a neuroscientist at the Mayo Clinic in Jacksonville (FL, USA), made the findings by studying hundreds of enzymes for the ability to lower beta-amyloid levels. BACE2 was found to lower beta-amyloid more effectively than all other enzymes tested. The finding is significant because BACE2 is closely related to another enzyme, known as BACE1, involved in producing beta-amyloid. “Despite their close similarity, the two enzymes have completely opposite effects on beta-amyloid--BACE1 giveth, while BACE2 taketh away,” Dr. Leissring noted.

Beta-amyloid is a fragment of a larger protein, known as amyloid precursor protein (APP), and is manufactured by enzymes that cut APP at two places. BACE1 is the enzyme responsible for making the first cut that generates beta-amyloid. The research showed that BACE2 cuts beta-amyloid into smaller pieces, thereby destroying it, instead. Although other enzymes are known to degrade beta-amyloid, BACE2 is particularly efficient at this function, the study found.

Earlier research had revealed that BACE2 can also lower beta-amyloid levels by a second mechanism: by cutting APP at a different region from BACE1. BACE2 cuts in the middle of the beta-amyloid portion, which prevents beta-amyloid production. “The fact that BACE2 can lower beta-amyloid by two distinct mechanisms makes this enzyme an especially attractive candidate for gene therapy to treat Alzheimer’s disease,” said first author Samer Abdul-Hay, PhD, a neuroscientist at Mayo Clinic in Florida.

The discovery suggests that faults in BACE2 might increase the risk of AD. This is important because certain drugs in clinical use--for example, antiviral agents used to treat human immunodeficiency virus (HIV)--work by inhibiting enzymes similar to BACE2.

Although BACE2 can decrease beta-amyloid by two distinct processes, only the newly discovered mechanism--beta-amyloid destruction--is probably relevant to the disease, the researchers noted. This is because the second mechanism, which involves BACE2 cutting APP, does not occur in the brain.

The researchers have obtained a grant from the US National Institutes of Health (Bethesda, MD, USA) to assess whether blocking beta-amyloid destruction by BACE2 can increase the risk for AD in a mouse model of the disease.

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