The Neuroprotective Effects of Berberine in Alzheimer's Disease Mouse Model via Improvement of Mitochondrial Dysfunction and Enhanced Amyloid-beta Peptide Clearance

Objectives: Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by mitochondrial impairment, abnormal accumulation of amyloid-beta (Aβ), and a gradual decline in cognitive function. Despite extensive research, effective therapeutic options remain limited, underscoring the need to explore novel strategies. Natural compounds have emerged as promising candidates due to their multitarget properties and favorable safety profiles. Among them, berberine, an isoquinoline alkaloid isolated from various medicinal plants, has attracted considerable attention for its antioxidant, anti-inflammatory, and metabolic regulatory activities. Importantly, berberine has been shown to activate AMP-activated protein kinase (AMPK), a central regulator of cellular energy homeostasis and mitochondrial biogenesis. Methods: In the present study, we evaluated the neuroprotective effects of oral berberine administration using an Aβ-induced AD mouse model. Cognitive functions were assessed by Y-maze and novel object recognition tests. Biochemical analyses were conducted to measure Aβ concentrations and the expression of mitochondrial regulatory proteins, including phosphorylated AMPK, sirtuin 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). Results: Berberine supplementation led to significant improvements in behavioral outcomes, attenuated Aβ deposition, and reinstated levels of phosphorylated AMPK, SIRT1, and PGC-1α. Conclusion: Overall, these results indicate that berberine confers neuroprotection via activation of the AMPK-SIRT1-PGC-1α signaling axis, underscoring its promise as a therapeutic agent for AD.