CNEURO-201, an Anti-Amyloidogenic Agent and σ1-Receptor Agonist Improves Cognition in the 3xTg Mouse Model of Alzheimer’s Disease by Multiple Actions in the Pathology

The complexity of Alzheimer’s disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits a great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other pathways related to this pathology remains to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg-1 (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system and glial cell activation related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques, but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in redox system. Our outcomes reinforced the potential of CN to treat AD by acting on multiple pathways altered in this disease.