Evaluation of betanin‐loaded liposomal nanocarriers in AlCl3‐induced Alzheimer's disease in rats: Impact on cognitive function, neurodegeneration, and TREM2/ADAM10 pathways

Abstract Betanin (BET) has been studied for its therapeutic benefits in various diseases, but its low bioavailability and uncertain brain penetration limit its efficacy. Accordingly, this study aimed to explore BET‐loaded liposomal nanocarriers (LPN) as a novel treatment for Alzheimer's disease (AD), focusing on the triggering receptor expressed on myeloid cells 2 (TREM2)/DNAX‐activating protein of 12 kDa (DAP12) and extracellular signal‐regulated kinase 1/2 (ERK1/2) pathways implicated in AD. In an AlCl 3 ‐induced AD rat model, 48 male Wistar rats were divided into four groups: control, AlCl 3 (50 mg/kg, intraperitoneal), AlCl 3 +BET (100 mg/kg, per os), and AlCl 3 +BET LPN (25 mg/kg, intranasally), with treatments administered for 28 days. Morris water maze test and histopathological examination showed that BET LPN‐treated rats had improved spatial and learning memory and less hippocampal and cortical degeneration compared with the AlCl 3 and oral BET groups. Mechanistically, BET LPN treatment corrected AD biomarkers, increased miR‐132 and ADAM10 expression, and reduced oxidative stress, inflammation, and apoptosis. Additionally, BET LPN treatment suppressed the expression of TREM2, DAP12, ERK1/2, and mitogen‐activated protein kinase 1/2 (MEK1/2), showing greater improvement than oral BET. These findings suggest that BET LPN enhances cognitive function and neuroprotection in AD by modulating miR‐132 and ADAM10 and inhibiting ERK1/2 and TREM2/DAP12 pathways, providing a more effective treatment compared with traditional oral BET administration.