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Goldhardt, O.* ; Robles, C.M.* ; Eberl, M.* ; Dreyer, T.F.* ; Soosaipillai, A.* ; Diamandis, E.P.* ; Priller, J.* ; Hoffmann, D. ; Wettengel, J.M. ; Bustamante, H.A.* ; Salazar, P.* ; Thaler, M.* ; Otth, C.* ; Ehrenfeld, P.* ; Grimmer, T.*

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

Alzheimers Res. Ther. 18:212 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Immune System ; Gene Knockdown ; Herpes Simplex Virus ; Disease ; Antibody ; Virus ; Pathophysiology ; Viral Replication; Amyloid-beta Peptides; Immunofluorometric Assay; Type-1; Brain; Dementia; Tau; Identification; Specificity; Inhibition; Expression
ISSN (print) / ISBN 1758-9193
e-ISSN 1758-9193
Journal Alzheimer's Research & Therapy
Quellenangaben Volume: 18, Issue: 1, Pages: , Article Number: 212 Supplement: ,
Publisher Springer
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Virology (VIRO)
Grants Technische Universitt Mnchen (1025)