Modulation of Mitochondrial Dynamics by Loganic Acid Ameliorates Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies.

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, which refers to forgetting facts and experiences. Apart from being a classical neuropathological hallmark, AD is connected with pronounced mitochondrial fragmentation, although the exact contribution of mitochondrial dynamics in AD progression is poorly defined. Therefore, this study is aimed at investigating the role of loganic acid (LGA) in mitochondrial dynamics, hippocampal plasticity, and cognitive deficits in the scopolamine (SC)-induced cognitive impairment model. The results showed significant decline of p-Drp1 protein and elevation of Mfn2 proteins in LGA-treated SC-induced mice, indicating reduced mitochondrial fragmentation and restoration of mitochondrial dynamics. In addition, LGA treatment promotes the reduction of fragmented and spherical-shaped mitochondria in SC-induced mice. LGA treatment alleviated reactive oxygen species (ROS) production and elevated mitochondrial membrane potential, reducing neurodegeneration in SC mice. Moreover, the decline of inflammatory cytokines (TNF-α and IL-1β) and downregulation of NF-kB expression in LGA-treated SC-induced mice suggested improved neuronal health. In parallel, LGA also increased the regulation of the cytoskeleton within neuronal dendrites, synaptic plasticity, and neuronal dendrites outgrowth, which was validated with increased expression of MAP2. In conclusion, the present study findings suggest that LGA exerts neuroprotection via preserving the mitochondrial ultrastructure and modulating the mitochondrial dynamics. All of these changes further restore neuronal cell density and myelination, leading to the mitigation of neurodegeneration, and restore cognitive deficits and spatial memory in SC-induced C57BL/6 mice.