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

作者：Wu Guoxin; Sankaranarayanan Sethu; Tugusheva Kate; Kahana Jason; Seabrook Guy; Shi Xiao ping; King Elizabeth; Devanarayan Viswanath; Cook Jacquelynn J; Simon Adam J^*

来源：Clinical Biochemistry, 2008, 41(12): 986-996.

DOI：10.1016/j.clinbiochem.2008.04.022

• BACE
• CSF
• Alzheimer's
• biomarker
• assay development

Objectives: 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.
Methods: 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.
Results: The CSF BACE-1 activity assay described exhibits time, temperature, dose, and pH dependence, with sensitivity down to < 1 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 (similar to 1.0 pM/year, p < 0.05). 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).
Conclusion: 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.

• 出版日期2008-8