Decrease in Brain Soluble Amyloid Precursor Protein β (sAPPβ) in Alzheimer's Disease Cortex

Amyloid-beta peptide (Ab) is generated by sequential cleavage of the amyloid precursor protein (APP) by beta-site amyloid precursor protein cleaving enzyme 1 (beta-secretase, or BACE1) and gamma-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 (sAPP beta). To relate BACE1 activity better to endogenous APP processing in AD and control brains, we have directly measured brain sAPP beta levels using a novel APP beta-site specific enzyme-linked immunosorbent assay. We demonstrate a significant reduction in brain cortical sAPP beta levels in AD compared with control subjects. In the same brain samples, BACE1 activity was unchanged, full-length APP and sAPP alpha levels were significantly reduced, and A beta peptides were significantly elevated. In conclusion, a reduction in cortical brain sAPP beta 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. (C) 2011 Wiley-Liss, Inc.