Changes in Glial Support of the Hippocampus during the Development of an Alzheimer’s Disease-like Pathology and Their Correction by Mitochondria-Targeted Antioxidant SkQ1

Abstract

Astrocytes and microglia are the first cells to react to neurodegeneration, e.g., in Alzheimer’s disease (AD); however, the data on changes in glial support during the most common (sporadic) type of the disease are sparse. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, and Wistar rats (parental normal strain, control), we investigated hippocampal neurogenesis and glial changes during AD-like pathology. Using immunohistochemistry, we showed that the early stage of the pathology is accompanied by a lower intensity of neurogenesis and decreased astrocyte density in the dentate gyrus. The progressive stage is concurrent with reactive astrogliosis and microglia activation, as confirmed by increased cell densities and by the acquisition of cell-specific gene expression profiles, according to transcriptome sequencing data. Besides, here, we continued to analyze the anti-AD effects of prolonged supplementation with mitochondria-targeted antioxidant SkQ1. The antioxidant did not affect neurogenesis, partly normalized the gene expression profile of astrocytes and microglia, and shifted the resting/activated microglia ratio toward a decrease in the activated-cell density. In summary, both astrocytes and microglia are more vulnerable to AD-associated neurodegeneration in the CA3 area than in other hippocampal areas; SkQ1 had an anti-inflammatory effect and is a promising modality for AD prevention and treatment.

The Rat Brain Transcriptome: From Infancy to Aging and Sporadic Alzheimer’s Disease-like Pathology

“…Some studies provide strong evidence that a decrease in Aβ clearance or a decrease in phagocytosis by microglia—rather than an Aβ peptide overproduction by cleavage of the APP—may be involved in AD [ 41 ]. In OXYS rats, Aβ accumulates with age, but its level in the brain increases most pronouncedly from the age of 1 year during a decrease in the expression of genes associated with Aβ clearance [ 20 , 26 ] and microglial hypofunction [ 23 , 42 , 43 ]. Here we noticed that at P3 and P10, DEGs in the PFC and hippocampus are related to Aβ binding and regulation of Aβ formation; at P10, DEGs in both brain regions are related to Aβ clearance.…”

Early-life stress exposure impacts the hippocampal synaptic proteome in a mouse model of Alzheimer’s disease: age- and pathology-dependent effects on mitochondrial proteins

“…At the same time, an imbalance in the synthesis of fatty acids may mean increased rates of oxidative stress, given their propensity to be peroxidized by free radicals (128). This seemed to occur predominantly in astrocytes, in line with the important role of their mitochondria in energy production (72,129).…”

Cellular Reprogramming and Its Potential Application in Alzheimer’s Disease

“…The common pathway of neuronal death in neurodegenerative diseases, including AD, is caused by oxidative stress, dysregulated calcium homeostasis, excess production of free radicals, and calcium overload, causing the disruption of mitochondrial membranes and mitochondrial dysfunction ( Egawa et al, 2020 ). While neurogenesis is a highly energy-intensive process, mitochondrial dysfunction can easily lead to neuronal death ( Rudnitskaya et al, 2022 ).…”