Amyloid β peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Aβ-mediated toxicity in vitro

The gradual accumulation and assembly of beta-amyloid (A beta) peptide into neuritic plaques is a major pathological hallmark of Alzheimer disease (AD). Proteolytic degradation of A beta is an important clearance mechanism under normal circumstances, and it has been found to be compromised in those with AD. Here, the extended substrate specificity and A beta-degrading capacity of kallikrein 7 (KLK7), a serine protease with a unique chymotrypsin-like specificity, was characterized. Preferred peptide substrates of KLK7 identified using a bacterial display substrate library were found to exhibit a consensus motif of RX Phi(Y/F)down arrow(Y/F)down arrow(S/A/G/T) or RX Phi(Y/F)down arrow(S/T/A) (Phi = hydrophobic), which is remarkably similar to the hydrophobic core motif of A beta (K16L17V18F19F20 A 21) that is largely responsible for aggregation propensity. KLK7 was found to cleave after both Phe residues within the core of A beta(42) in vitro, thereby inhibiting A beta fibril formation and promoting the degradation of preformed fibrils. Finally, the treatment of A beta oligomer preparations with KLK7, but not inactive pro-KLK7, significantly reduced A beta(42)-mediated toxicity to rat hippocampal neurons to the same extent as the known A beta-degrading protease insulin-degrading enzyme (IDE). Taken together, these results indicate that KLK7 possesses an A beta-degrading capacity that can ameliorate the toxic effects of the aggregated peptide in vitro.