KBN2201 attenuates Aβ pathology and neuroinflammation while promoting neuroprotective and neurogenesis-related changes in a late-stage 5xFAD mouse model of Alzheimer's disease.

Abstract

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, neuronal loss, and cognitive decline. Here, we report that KBN2201, a derivative of 2-hydroxy-4-(trifluoromethyl)benzoic acid, exerts multi-target effects in 5xFAD mice. To evaluate its efficacy at a late disease stage, daily oral administration of KBN2201 (5 or 20 mg/kg) was initiated in 9-month-old 5xFAD mice and continued for three months. KBN2201 significantly reduced hippocampal amyloid precursor protein C-terminal fragments (APP-CTFs), indicating decreased accumulation of APP-derived fragments. In addition, KBN2201 lowered insoluble Aβ42 levels, supporting on overall reduction in amyloid burden. The compound also reduced both fibrillar and total Aβ plaque burden in the cortex and hippocampus, as demonstrated by thioflavin S and 4G8 staining. Astrocytic and microglial activation was significantly suppressed. Preservation of the hippocampal CA1 region and cortical dendritic structure was observed. In addition, markers associated with neurogenesis were increased in the subventricular zone (SVZ) and hippocampus, as indicated by elevated Ki67 and doublecortin (DCX) levels. These effects were accompanied by improved spatial working memory in the Y-maze test and enhanced recognition memory in the novel object recognition (NOR) test, with greater effects observed at the 5 mg/kg dose. Together, these findings suggest that KBN2201 mitigates AD-related pathology and improves cognitive function, supporting its potential as a multi-target therapeutic candidate for AD.