Herpes simplex virus and kallikrein-related peptidases – a functional connection in Alzheimer‘s disease

Abstract Background The viral hypothesis of Alzheimer’s disease (AD) proposes that neurotropic pathogens may interact with amyloid and tau pathology, but the evidence remains controversial. We investigated whether cerebrospinal fluid (CSF) kallikrein-related peptidase 6 (KLK6) is associated with AD biomarkers and with an intrathecal anti-HSV immune response in patients with AD, and whether HSV-1 infection alters KLK6 expression in cell culture models. Methods CSF KLKs and AD biomarkers were analyzed in patients with AD. HSV-1 serostatus and anti-HSV-1/2 CSF-to-serum antibody index (HSV-AI) were used as markers of previous or ongoing intrathecal anti-HSV immune response. In vitro, HSV-1 infection and KLK6 knockdown were examined in human cell models. Results CSF-KLK6 correlated with tau and amyloid biomarkers. In HSV-1-seropositive patients, HSV-AI was associated with CSF-KLK6, although the effect size was modest and the association was strongly context-dependent on the Aβ42/40 ratio. In vitro, productive HSV-1 infection induced and stabilized KLK6 protein expression, and KLK6 knockdown reduced HSV-1 protein expression and infectious progeny in HaCaT cells. Conclusions: KLK6 is associated with AD biomarkers and with an intrathecal anti-HSV immune response in a subset of patients with AD. The in vitro data support a functional relationship between HSV-1 infection and KLK6, but the clinical findings are associative and do not demonstrate ongoing CNS HSV-1 replication or causality. These findings warrant independent validation. However, this research provides further evidence for a role of HSV-1 in the pathophysiology of AD.