Decrease in brain soluble amyloid precursor protein β (sAPPβ) in Alzheimer's disease cortex

• Published in: Journal of neuroscience research 2011-06, Vol.89 (6), p.822-832
• Main Authors: Wu, Guoxin, Sankaranarayanan, Sethu, Hsieh, Sidney H.-K., Simon, Adam J., Savage, Mary J.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - metabolism; APP; Aspartic Acid Endopeptidases - metabolism; BACE; biomarker; Cerebral Cortex - metabolism; ELISA; Enzyme-Linked Immunosorbent Assay - methods; Female; Humans; Male; Peptide Fragments - metabolism; Phosphorylation; sAPPβ; tau Proteins - metabolism; Threonine - metabolism
• ISSN: 0360-4012; 1097-4547; 1097-4547
• DOI: 10.1002/jnr.22618

Amyloid‐β peptide (Aβ) is generated by sequential cleavage of the amyloid precursor protein (APP) by β‐site amyloid precursor protein cleaving enzyme 1 (β‐secretase, or BACE1) and γ‐secretase. Several reports demonstrate increased BACE1 enzymatic activity in brain and cerebrospinal fluid (CSF) from Alzheimer's disease (AD) subjects, suggesting that an increase in BACE1‐mediated cleavage of APP drives amyloid pathophysiology in AD. BACE1 cleavage of APP leads to the generation of a secreted N‐terminal fragment of APP (sAPPβ). To relate BACE1 activity better to endogenous APP processing in AD and control brains, we have directly measured brain sAPPβ levels using a novel APP β‐site specific enzyme‐linked immunosorbent assay. We demonstrate a significant reduction in brain cortical sAPPβ levels in AD compared with control subjects. In the same brain samples, BACE1 activity was unchanged, full‐length APP and sAPPα levels were significantly reduced, and Aβ peptides were significantly elevated. In conclusion, a reduction in cortical brain sAPPβ together with unchanged BACE1 activity suggests that this is due to reduced full‐length APP substrate in late‐stage AD subjects. These results highlight the need for multiparameter analysis of the amyloidogenic process to understand better AD pathophysiology in early vs. late‐stage AD. © 2011 Wiley‐Liss, Inc.