Neuroinflammation is a central feature of Alzheimer's disease (AD), yet the mechanisms linking inflammatory protease systems to disease pathology remain incompletely understood. The kallikrein-kinin system (KKS), a major source of bradykinin, has been associated with AD mainly at the peripheral level, but its regulation within the human brain remains largely unexplored. Here, we investigated KKS activity in human AD tissue and a transgenic mouse model, with a particular focus on serine protease kallikrein-8 (KLK8). We observed that both bradykinin and bradykinin B1 receptor levels are increased in the hippocampus of AD patients, with a pronounced upregulation in females. In the TgCRND8 mouse model of AD, hippocampal bradykinin levels were also elevated, while heterozygous KLK8 knockout ameliorated this pathological effect, supporting a functional contribution of KLK8. Analysis of kallikrein expression revealed a selective increase in KLK8 in the AD hippocampus, whereas the canonical kinin-generating proteases, tissue kallikrein (KLK1) and plasma kallikrein (KLKB1), remained unchanged. In vitro cleavage assays demonstrated that recombinant human KLK8 can process both low- and high-molecular-weight kininogens, and functional assays confirmed that KLK8 increases bradykinin levels in human hippocampal tissue and plasma, an effect that was blocked by a KLK8-neutralizing antibody. Together, these findings identify KLK8 as a previously unrecognized modulator of the KKS in the AD brain. Our data support a model in which elevated KLK8 contributes to dysregulated bradykinin production and B1R signaling, providing a mechanistic link between KLK8 activity and neuroinflammation in Alzheimer's disease. • Kallikrein-kinin system activity is increased in Alzheimer's affected brain. • KLK8, but not KLK1 or KLKB1, is elevated in Alzheimer's brain. • KLK8 cleaves kininogens and drives bradykinin generation. • Bradykinin receptor B1R is increased in female AD hippocampus. • Genetic knockdown of KLK8 lowers hippocampal bradykinin in AD mice.
Raza et al. (Fri,) studied this question.