Treatment with KCL-286, a first-in-class retinoic acid receptor-β (RARβ) agonist, ameliorates neuronal DNA damage and inflammation in a mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder for which effective disease-modifying therapies remain limited. Accumulation of neuronal DNA double-strand breaks (DSBs) is an early pathological event that contributes to genomic instability and neuronal vulnerability in AD. Therapeutic strategies that enhance DNA repair may therefore be of considerable interest. Here, using the Tg2576 mouse model of AD, we show that treatment with KCL-286, a selective retinoic acid receptor-β (RARβ) agonist, reduces neuronal DNA damage. KCL-286 enhances DSB repair in neurons, in part through upregulation of the DNA repair factor BRCA1, while also attenuating neuroinflammatory activation. In addition, KCL-286 normalises microglial and astrocytic morphology, consistent with reduced pathological glial activation. Together, these findings demonstrate that selective RARβ activation ameliorates neuronal DNA damage and neuroinflammation in a mouse model of AD, supporting further investigation as a potential disease-modifying therapeutic strategy.