Decrease in age-adjusted cerebrospinal fluid beta-secretase activity in Alzheimer's subjects

To develop a novel cerebrospinal fluid (CSF) beta-secretase-1 activity assay and evaluate beta-secretase-1 (BACE-1) activity as a potential biomarker in human Alzheimer's disease.The assay consisted of an enzymatic reaction of CSF samples with an optimized beta-secretase peptide substrate and the cleavage products were detected using a neo-epitope specific antibody.The CSF BACE-1 activity assay described exhibits time, temperature, dose, and pH dependence, with sensitivity down to1 pM of recombinant BACE-1 enzyme, and is completely blocked by BACE-1 inhibitors. The endogenous BACE-1 enzyme in CSF appears to exist as a c-terminally truncated protein, based on both western blotting and capture-based activity assays. In a small cohort of human subjects, an age-dependent increase in CSF BACE activity was observed (~1.0 pM/year, p0.05). In Alzheimer's disease subjects, a significant decline in age-adjusted CSF BACE activity was observed compared to controls (56% in the log-transformed scale, p=0.02).We have developed a robust assay to measure CSF BACE-1 activity which could serve as a potential biomarker in human Alzheimer's disease subjects.