Honokiol relieves hippocampal neuronal damage in Alzheimer’s disease by activating the SIRT3-mediated mitochondrial autophagy

Background
This study explored the impact of honokiol (HKL) on mitochondrial function in hippocampal neurons in the context of Alzheimer’s disease (AD).

Methods
APP/PS1 mice were utilized as models of AD and were treated with HKL and 3-TYP. Cognitive performance was assessed using the Morris water maze test. Immunohistochemistry and Nissl staining were employed to evaluate Aβ+ plaque deposition and neuronal survival in the hippocampus. Hippocampal neurons were isolated from C57BL/6 mouse embryos, and an AD model was created by inducing Aβ oligomers, followed by treatment with HKL, CsA, and 3-TYP. Neuronal viability and apoptosis were measured using the cell counting kit-8 assay and TUNEL staining. To monitor neuronal autophagosomes, mitochondrial reactive oxygen species (ROS), neuronal ROS, and mitochondrial membrane potential, mRFP-eGFP-LC3 assays, MitoSOX Red, dichlorodihydrofluorescein diacetate, and JC-1 staining were conducted. Autophagy-related proteins were analyzed via Western blot.

Results
In AD mice, HKL enhanced cognitive function, reduced Aβ1-42 plaque deposition in the hippocampus, promoted neuron survival, and stimulated SIRT3 expression and mitochondrial autophagy. However, the beneficial effects of HKL were negated by 3-TYP treatment. In the hippocampal neuronal AD model, HKL increased neuronal activity, decreased apoptosis and Aβ aggregation, activated SIRT3 and mitochondrial autophagy, lowered mitochondrial and neuronal ROS levels, and improved mitochondrial membrane potential. The protective effects of HKL were abolished by CsA and 3-TYP treatments, with 3-TYP also counteracting HKL’s promotion of mitochondrial autophagy.

Conclusions
HKL activates SIRT3-mediated mitochondrial autophagy, helping to reduce damage to hippocampal neurons in AD. These findings suggest that HKL may hold promise as a therapeutic agent for treating Alzheimer’s disease.