KBN2202, a Salicylic Acid Derivative, Preserves Neuronal Architecture, Enhances Neurogenesis, Attenuates Amyloid and Inflammatory Pathology, and Restores Recognition Memory in 5xFAD Mice at an Advanced Stage of AD Pathophysiology

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, amyloid-β (Aβ) pathology, synaptic degeneration, impaired neurogenesis, and chronic neuroinflammation. KBN2202, a small-molecule salicylic acid derivative [2-[(2-naphthalen-1-yloxy)ethyl]amino]-4-hydroxybenzoic acid], was investigated for its potential as a multi-target therapeutic agent in advanced-stage AD. To this end, 9-month-old 5xFAD mice with established AD-like pathology received daily oral KBN2202 (5 or 20 mg/kg) or vehicle for 12 weeks. KBN2202 demonstrated broad histopathological benefits. It preserved hippocampal CA1 cytoarchitecture and increased dendritic length in cortical neurons. Neurogenic activity was also enhanced, with elevated doublecortin (DCX) expression in the subventricular zone (SVZ). At the molecular level, KBN2202 reduced amyloid precursor protein C-terminal fragments (APP-CTFs), key intermediates in amyloidogenic processing, and histological staining confirmed a significant reduction in fibrillar and diffuse Aβ plaque burden in the cortex and hippocampus. Furthermore, KBN2202 attenuated astrocytic and microglial activation, indicating suppression of chronic neuroinflammation. In behavioral assessments, KBN2202 significantly improved recognition memory in the novel object recognition (NOR) test, while Y-maze performance remained unchanged. Overall, the compound exhibited robust neuroprotective, pro-neurogenic, anti-amyloid, and anti-inflammatory effects. These findings support the therapeutic potential of KBN2202 as a multi-functional candidate for symptomatic-stage AD.