The proteins BACE1 and BACE2 and beta-secretase activity in normal and Alzheimer's disease brain

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the approximately 4.5 kDa protein fragment called Abeta (amyloid beta-peptide). Abeta is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as beta- and gamma-secretase. beta-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Abeta and was identified 7 years ago as BACE1 (beta-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of beta-secretase in the normal and AD brain are central to the understanding of excessive production of Abeta in AD, and in targeting and normalizing this beta-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased beta-secretase activity in AD, with recent findings by our group showing changes in beta-secretase enzyme kinetics in AD brain caused by an increased V(max). This article gives a brief review of studies which have examined BACE1 protein levels and beta-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.