Journal Article

DZNE-2026-01013

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Herpes simplex virus and kallikrein-related peptidases - a functional connection in Alzheimer's disease.

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

2026
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s13195-026-02204-3

Abstract: 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.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.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.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.

Keyword(s): Humans (MeSH) ; Alzheimer Disease: cerebrospinal fluid (MeSH) ; Alzheimer Disease: virology (MeSH) ; Alzheimer Disease: enzymology (MeSH) ; Kallikreins: cerebrospinal fluid (MeSH) ; Kallikreins: genetics (MeSH) ; Kallikreins: metabolism (MeSH) ; tau Proteins: cerebrospinal fluid (MeSH) ; Amyloid beta-Peptides: cerebrospinal fluid (MeSH) ; Female (MeSH) ; Male (MeSH) ; Aged (MeSH) ; Biomarkers: cerebrospinal fluid (MeSH) ; Herpesvirus 1, Human: immunology (MeSH) ; Aged, 80 and over (MeSH) ; Peptide Fragments: cerebrospinal fluid (MeSH) ; Herpes Simplex: cerebrospinal fluid (MeSH) ; Animals (MeSH) ; RNA, Small Interfering: metabolism (MeSH) ; Alpha-herpesvirinae ; Alzheimer’s disease ; HSV1 ; Herpes simplex virus type 1 ; KLK6 ; Kallikrein-related peptidase ; Phospho tau ; Soluble amyloid ; Total tau ; Kallikreins ; tau Proteins ; Amyloid beta-Peptides ; KLK6 protein, human ; Biomarkers ; amyloid beta-protein (1-42) ; Peptide Fragments ; amyloid beta-protein (1-40) ; RNA, Small Interfering

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Contributing Institute(s):

1. Translational Neuropsychiatry (AG Priller)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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