Beta‐secretase regulation in aging and disease

Abstract

Background: Beta-secretase (BACE, types 1 and 2) has been identified as the enzyme that cleaves the β-amyloid Precursor Protein to form the amyloid-β peptide (Aβ). As the Aβ peptide is considered a primary causal factor in Alzheimer's disease (AD) pathogenesis, reducing Aβ production is currently a major therapeutic goal. In several disease states, as with normal aging, BACE protein and activity is increased in affected tissues. Therefore, determination of what regulates BACE is of critical importance. We sought to characterize one possible candidate. Objective: To determine the role of BACE in disease pathology, as it relates to levels of cellular nucleic acid binding protein (CNBP), a candidate regulatory factor. Methods: A fluorometric BACE assay was developed, validated, and optimized. Using this assay and Western Blot, BACE enzymatic activity and protein levels were measured in aging mice, and in human AD and age-matched control tissue. Results: Cell culture studies demonstrate that CNBP regulates BACE protein and activity at the mRNA level. A BACE assay was developed to measure BACE1/2 activation in vivo as related to CNBP levels. CNBP levels and BACE activity were then measured in aging and diseased tissue, which showed a tendency for CNBP to increase with age. These data suggest CNBP may regulate BACE in vivo and in vitro, and may contribute to the development of AD and other age-related degenerative diseases.