Role of Retinoic Acid Receptor β Signalling in Alzheimer’s Disease

Abstract

Alzheimer's disease, the most common form of Dementia, is characterized by a debilitating progression of memory impairment and cognitive decline. The distinct neuropathological hallmarks characterizing Alzheimer's disease revolve around the existence of senile plaques containing amyloid-β, as well as neurofibrillary tangles composed of tau protein, precipitating oxidative stress and neuroinflammation. The therapeutic options for Alzheimer’s disease are either symptomatic treatments or disease-modifying drugs, with the latter currently showing significant investment in targeting amyloid-β. Interestingly, DNA double-strand breaks play a role in increasing the secretion of amyloid-β, consequently triggering the aggregation of amyloid-β plaques. However, there are currently no therapeutic options available for Alzheimer’s disease that specifically target the induction of DNA repair. KCL286, a synthetic retinoic acid receptor beta agonist with promising results from a phase I clinical trial, has demonstrated its capacity to initiate DNA repair mechanisms in a nerve injury model. In this context, we embarked upon an investigation into the effects of KCL286 administration in Tg2576 mice, a transgenic strain characterized by human amyloid precursor protein overexpression and consequently amyloid-β accumulation. A three-month treatment significantly reduced the DNA damage response protein γH2AX, in particular the gene expression of γH2AX within the hippocampus. The inducing of DNA double-strand break repair corresponded with the clearance of amyloid-β deposits and reduction in inflammation. The study underscores the potential of stimulating the RARβ signalling pathway via the RARβ agonist KCL286, as it appears to induce DNA repair mechanism and amyloid-β clearance. This reinforces the drug’s promise as a prospective therapeutic candidate for Alzheimer's disease.