title: Characterization of plasma β-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer's disease.
abstract: Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho-thr181 tau consistently differentiate between Alzheimer's disease (AD) and age-matched control subjects. In contrast, CSF β-site APP-cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age-matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1-specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ-secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age-matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies.
authors.affiliation: Department of Molecular Biomarkers, Merck Research Laboratory, West Point, Pennsylvania, USA. guoxin_wu@merck.com
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Jacky
authors.initials: J
authors.lastname: Wong
authors.forename: Katherine
authors.initials: K
authors.lastname: Tugusheva
authors.forename: Maria S
authors.initials: MS
authors.lastname: Michener
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Shi
authors.forename: Jacquelynn J
authors.initials: JJ
authors.lastname: Cook
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Savage
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000097:blood* / Q000175:diagnosis; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000097:blood* / Q000172:deficiency; D016229:Amyloid beta-Peptides / Q000097:blood*; D016564:Amyloid beta-Protein Precursor / Q000097:blood*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000097:blood* / Q000172:deficiency; D015415:Biomarkers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000097:blood*; D012680:Sensitivity and Specificity; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C510791:MRK 560; D010446:Peptide Fragments; D013449:Sulfonamides; C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse