Amyloid ß peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Aß-mediated toxicity in vitro.

The gradual accumulation and assembly of ß-amyloid (Aß) peptide into neuritic plaques is a major pathological hallmark of Alzheimer disease (AD). Proteolytic degradation of Aß 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 Aß-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 RXΦ(Y/F)↓(Y/F)↓(S/A/G/T) or RXΦ(Y/F)↓(S/T/A) (Φ=hydrophobic), which is remarkably similar to the hydrophobic core motif of Aß (K16L17V18F19F20 A21) that is largely responsible for aggregation propensity. KLK7 was found to cleave after both Phe residues within the core of Aß42 in vitro, thereby inhibiting Aß fibril formation and promoting the degradation of preformed fibrils. Finally, the treatment of Aß oligomer preparations with KLK7, but not inactive pro-KLK7, significantly reduced Aß42-mediated toxicity to rat hippocampal neurons to the same extent as the known Aß-degrading protease insulin-degrading enzyme (IDE). Taken together, these results indicate that KLK7 possesses an Aß-degrading capacity that can ameliorate the toxic effects of the aggregated peptide in vitro.