title: Decrease in age-adjusted cerebrospinal fluid beta-secretase activity in Alzheimer's subjects.
abstract: OBJECTIVE
  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 (~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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Alzheimer's Research, Merck Research Laboratory, West Point, PA, USA.
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Kate
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Jason
authors.initials: J
authors.lastname: Kahana
authors.forename: Guy
authors.initials: G
authors.lastname: Seabrook
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Shi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: King
authors.forename: Viswanath
authors.initials: V
authors.lastname: Devanarayan
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D008875:Middle Aged; D010436:Pepstatins / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012680:Sensitivity and Specificity
chemical_list: D010436:Pepstatins; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C031375:pepstatin