Methylprednisolone alleviates cognitive functions through the regulation of neuroinflammation in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and linked to abnormal deposition of amyloid-β (Aβ), neurofibrillary tangles (NFTs), synaptic dysfunction, and neuroinflammation. Despite significant progress in unravelling the pathogenesis of AD, currently main therapeutic interventions is limited to symptomatic alleviation. Methylprednisolone (MP), a synthetic glucocorticoid, is recognized for its extensive anti-inflammatory properties. Our study assessed the neuroprotective effect of MP (25 mg/kg) administration to an Aβ_1-42-induced AD mouse model. Our findings demonstrate that MP treatment can ameliorate cognitive impairment in Aβ_1-42-induced AD mice and suppress microglial activation in the cortex and hippocampus. RNA-Sequencing analysis reveals that MP ultimately rescues cognitive dysfunction through improving the synapse function and inhibiting the immune and inflammatory processes. Our study suggests that MP could be a promising drug alternative for the treatment of AD, either alone or in combination with other existing drugs.

Keywords: Alzheimer’s disease; cognitive function; methylprednisolone; microglial activation; neuroinflammation.

Figure 1

MP can alleviate cognitive dysfunction in Aβ_1-42-induced mice. Once injected with Aβ_1-42 (10 ug, 5 uL, i.c.v.), the mice were treated with MP (25 mg/kg, i.g.). (A) Schematic of experimental design. (B) The spontaneous alternation performance in the Y-maze test. (C) Path length of each group. (D) Average swimming speed of each group. (E) Spent time in the target quadrant at the last exploration trial. (F) The latency to find the target platform during training trials and the last exploration trail. (G) The swimming paths of mice finding the hidden platform at the last exploration trial. Data are shown as mean ± SEM (n=10). *P < 0.05 vs. control group; ^#P < 0.05 vs. Aβ_1-42-induced group.

Figure 2

MP inhibits the excessive activation of microglia in the cortex and hippocampus of AD mice. (A) Representative fluorescence micrographs showing iBA1 expression in the cortex (Scale bar, 1000 μm). (B) Quantification of the total number of iBA1⁺ cells in the cortex (n = 3). (C) Representative fluorescence micrographs showing iBA1 expression in the hippocampus (Scale bar, 1000 μm). (D) Quantification of the total number of iBA1⁺ cells in the hippocampus. (n = 3). (E) Representative fluorescence micrographs showing iBA1 expression in DG (Scale bar, 200 μm). Data are shown as mean ± SEM (n = 3). *P < 0.05 vs. control group; ^#P < 0.05 vs. Aβ_1-42-induced group.

Figure 3

MP altered mRNA expression profile of Aβ_1-42-induced mice. (A) Schematics of the experimental design. (B) Heatmap of DGEs in MP-treated Aβ_1-42-induced mice and the control Aβ_1-42-induced mice. (C) KEGG annotation for the differentially expressed genes. (D) GO enrichment analysis of DEGs and functional analysis for genes. (E) Hub genes identified from the PPI network based on the MCC algorithm in cytoHubba. (F) Quantified image shows the mRNA expression level of genes associated with synaptic function. (G) Quantified image shows the mRNA expression level of genes associated with immune response. Data are shown as mean ± SEM (n = 3). ^#P < 0.05 vs. Aβ_1-42-induced group.

Figure 4

A schematic representation of MP treatment alleviating cognitive dysfunction in AD nice. The administration of MP suppresses microglial activation and immune response, causing proinflammatory factors inhibition. Meanwhile, MP improves synaptic function by regulating the expression of the related genes. Altogether MP ameliorates recognition deficiency induced by Aβ_1-42 in mice.