Is alteration of ERK1/2 and p38MAPK signaling pathways activity a general mechanism of Alzheimer’s disease and age-related macular degeneration development?

Abstract

Age is the primary risk factor for Alzheimer’s disease (AD), the most prevalent progressive senile dementia, and age-related macular degeneration (AMD), the main cause of vision loss in individuals over 60. Effective prevention and treatment of these neurodegenerative conditions are lacking due to incomplete knowledge of their pathogenesis. Risk factors such as smoking, hypertension, hypercholesterolemia, atherosclerosis, obesity, and malnutrition intersect with the pathogenesis mechanisms of both AD and AMD. Oxidative stress, inflammation, mitochondrial dysfunction, and impaired proteostasis maintenance are among the pathological factors associated with the aggregation and accumulation of abnormal extracellular deposits — senile plaques in the brains of AD patients and drusen in AMD patients. Alterations in the regulation of MAPK signaling pathways with age may be associated to the emergence of these abnormalities. Impaired MAPK signaling was confirmed as a significant contributor to the pathogenesis of AD through the results of numerous investigations. MAPK is a potential target for therapeutic interventions. Information on its age-related changes, however, is limited. Virtually no data exist on retinal MAPK activity during AD and AMD development. This study aims to compare changes in ERK1/2 and p38MAPK signaling activity in brain and retina structures with age and AD/AMD progression. Wistar and OXYS rats were used as models of accelerated aging that show concomitant signs of AD and AMD. At the initial stage of the study, we examined the gene expression related to ERK1/2 and p38MAPK signaling pathways via comparing the transcriptomes (RNA-seq data) of the retina, prefrontal cortex, and hippocampus of OXYS and Wistar rats. The analysis was conducted when the rats were 20 days old and showed no signs of AMD and AD symptoms, during their manifestation period (age 3–5 months) and active progression stage (age 18 months). Changes in gene expression, involved in EPK1/2 [1] and p38MAPK signaling pathways according to the Rat Genome Database, are tissue-specific and dependent on the animal genotype. In the retina, the number of genes associated with ERK1/2 and p38MAPK decreased in both Wistar and OXYS rats with age and was minimal at 18 months of age. The greatest differences in the expression levels of these genes were detected when the rats were 20 days old, at the preclinical stage of AMD-like pathology development in OXYS rats. Both activators and inhibitors of the EPK1/2 and p38MAPK pathways were present among the differentially expressed genes (DEGs) with increased mRNA levels. At 3 months, the number of DEGs decreased, while activator genes predominated among those with increased mRNA levels. At 18 months, the retina of OXYS rats displayed only signs of decreased activity in signaling pathways at the gene expression level. Age-related changes in gene expression profiles related to the ERK1/2 [2] and p38MAPK [3, 4] signaling pathways in Wistar rats differed between brain structures and the retina. In the prefrontal cortex and hippocampus, the number of genes increased with age, and the expression differed between OXYS and Wistar rats. However, no signs of significant activation of the signaling pathway were observed. The phosphorylation level of ERK1/2 and p38MAPK signaling pathway kinases serves as an objective indicator of their activity. For protein level evaluation via Western blot analysis, we examined these levels in the retina, prefrontal cortex, and hippocampus. In both rat strains, a significant increase in phosphorylated forms of ERK1/2 and p38MAPK was observed with aging in all examined tissues. Simultaneously, accumulation of the substance became more active in OXYS rats and increased with progression of AD and AMD symptoms. Therefore, the results indicate that no significant changes in the activity of ERK1/2 and p38MAPK signaling cascades in the retina and brain structures are observed during normal aging of Wistar rats and accelerated aging of OXYS, both at the gene expression and protein level. AD and AMD pathological signs in OXYS rats were found to be associated with increased phosphorylation of ERK1/2 and p38MAPK, suggesting that enhancement of MAPK pathways may be a common mechanism for the early development of AD and AMD.