Specific inhibition of β-amyloid peptide secretion by ZK808762 mimicks the effect of non-steroidal anti-inflammatory drugs

Targeting the deposition of β-amyloid into neuritic plaques has been suggested as a pharmacological approach to alter the progression of Alzheimer disease (AD). Some non-steroidal anti-inflammatory drugs (NSAID) were recently shown to specifically inhibit the secretion of the highly amyloidogenic β-amyloid (Aβ) peptide Aβ1–42 independently of cyclooxygenase inhibition. Using cultures of chicken telencephalic neurons, we studied endogenous β-amyloid precursor protein processing, Aβ peptide formation and its pharmacological modulation by quantitative Aβ-SDS-PAGE/immunoblot and by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Aβ peptides Aβ1–40/42 and three additional C-truncated species, namely Aβ1–37/38/39 were regularly released into the culture medium strongly resembling the highly conserved Aβ quintet pattern found in human cerebrospinal fluid. ZK808762, a factor Xa and serine protease inhibitor, dose-dependently induced a specific decrease in secreted Aβ1–42, a marked elevation of Aβ1–38 and, to a lesser extend, Aβ1–37. Aβ1–40 and the total amount of secreted Aβ peptides remained unaffected. This pattern mimicks the effect of NSAID on Aβ secretion. The α-secretase pathway was not affected. Coincubation of ZK808762 and sulindac sulfide had an additive effect on Aβ secretion. Serine protease inhibitors might be useful as pharmacological modulators of Aβ peptide formation and as tools to study the pathophysiology of AD.