CNEURO-201 COUNTERACTS ALZHEIMER’S-LIKE COGNITIVE DECLINE AND PLASTICITY DEFICITS IN 3XTG-AD MICE

Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive functions, including spatial memory, which is essential for orientation and environmental navigation. Hippocampal dysfunction and synaptic plasticity alterations are strongly associated with cognitive impairment in AD, making the preservation of neural plasticity a relevant therapeutic target. CNEURO-201 (CN) is a novel compound with dual anti-amyloid and σ1 receptor agonist properties that has shown short-term cognitive benefits in AD mouse models at low doses. However, its long-term effects on memory and structural plasticity remain unclear. This study evaluated whether sustained CN administration could delay cognitive decline and
preserve dendritic spine density in the hippocampal CA1 subregion of the 3xTg mouse model of AD. Six-month-old female wild-type (WT) and 3xTg mice were treated orally for 24 weeks with CN (0.1 mg/kg) or vehicle. Spatial memory was assessed every eight weeks during treatment, and dendritic spine density was quantified at study completion using Golgi–Cox staining followed by morphometric analysis. Vehicle-treated 3xTg mice exhibited a progressive reduction in discrimination index values across time points, indicating spatial memory impairment. In contrast, CN-treated 3xTg mice showed a significant delay in memory decline, with performance comparable to WT controls at later stages. Moreover, CN treatment preserved dendritic spine density in the CA1 region relative to vehicle-treated transgenic mice. These findings indicate that long-term CN administration attenuates spatial memory decline in female 3xTg-AD mice and suggest that preservation of hippocampal structural plasticity may underlie its disease-modifying effects.