¹Karolinska Institutet, Physiology and Pharmacology, Stockholm, Sweden, ²Science for Life Laboratory, Organic Chemistry, Stockholm, Sweden

Background: Elevated central levels of kynurenic acid (KYNA) are associated with psychosis and cognitive deficits. KYNA is synthesized by four kynurenine aminotransferase (KAT I-IV) enzymes, among which KAT II is considered the primary enzyme under physiological conditions. During immune activation, pro-inflammatory cytokines induce the kynurenine pathway, including the synthesis of KYNA.

Aims & Objectives: The overarching aim of this study was to define the role of KAT III in inflammation-associated cognitive dysfunction and to distinguish its contribution from that of the related enzyme KAT II in regulating KYNA levels in the brain.
Specifically, we sought to: (i) assess KAT II and KAT III expression in human brain transcriptomic datasets from disorders associated with cognitive impairment; (ii) examine the relationship between inflammation and KAT II/KAT III expression and their synaptic relevance; (iii) identify disease.relevant cell types exhibiting KAT III upregulation; and (iv) validate inflammation-driven regulation of KAT III and the functional role of KAT II using in vitro and in vivo models.

Method: Publicly available bulk and single-cell RNA-sequencing datasets from postmortem human brain tissue were analyzed to assess KAT II and KAT III expression in infectious and psychiatric disorders associated with cognitive dysfunction. Correlation and network analyses were performed to examine relationships between inflammatory markers, KAT II/KAT III expression, and synaptic gene networks, alongside cell-type-specific expression profiling. Experimental validation was conducted using human-derived monocytes stimulated with Poly(I:C), as well as immune-challenged rodents, kynurenine-treated rodents, pharmacological KAT II inhibition, and KAT II knockout mice.

Results: Across datasets, KAT III was consistently upregulated in postmortem brain tissue from individuals with infectious or psychiatric disorders, with inflammatory markers positively correlating with KAT II and KAT III expression. Network analysis identified KAT III as occupying a more central synaptic role than KAT II, and single-cell analyses revealed KAT III upregulation in neurogranin-expressing neurons and oligodendrocyte progenitor cells upon COVID-19 infection. Experimentally, KAT III expression was increased in Poly(I:C)-stimulated human monocytes and in immune-challenged rodents, accompanied by elevated KYNA levels. In contrast, physiological increases in KYNA induced by kynurenine administration did not upregulate KAT III, and neither pharmacological KAT II inhibition nor genetic deletion of KAT II altered KYNA levels in immune-challenged rodents.

Discussion & Conclusions: Together, these findings identify KAT III as the key enzyme driving KYNA production during immune activation, and position KAT III as a promising therapeutic target for cognitive impairment associated with immune-mediated conditions.