ABSTRACT
Adult neurogenesis is one of the key mechanisms of the brain plasticity. Increase in the number of cells participating in the rearrangement of the neuronal circuits and synaptic formation facilitates the increase of brain's functional capacity. However, aging as well as neurodegenerative disorders lead to the disruption of the neurogenic niche microenvironment and the loss of molecular control, which in turn results in the significant decline of the neurogenesis. These events may contribute to the cognitive decline and the consequent development of dementia. Alzheimer's disease is a progressive incurable age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia. Hippocampus and entorhinal cortex are the key neurogenic niches in the adult brain and one of the most vulnerable brain areas during the development of Alzheimer's disease. Thus, neurodegeneration associated with the development of Alzheimer's disease affects adult neurogenesis. However, to date the mechanisms underlying this connection are unclear, and the investigation of these mechanisms is a promising strategy to find the approaches to correct the Alzheimer's disease pathology.
Subject(s)
Alzheimer Disease , Aged , Aging , Hippocampus , Humans , Neurogenesis , NeuronsABSTRACT
Alzheimer's disease (AD) is the most common type of age-related dementia. The development of neurodegeneration in AD is closely related to alterations in neurotrophic supplementation of the brain, which may be caused either by disorder of neurotrophin metabolism or by modification of its availability due to changes in the microenvironment of neurons. The underlying mechanisms are not fully understood. In this work, we used senescence-accelerated OXYS rats as a unique model of the sporadic form of AD to examine the relationship of development of AD signs and changes in neurotrophic supplementation of the cortex. Based on comparative analysis of the transcriptome of the frontal cerebral cortex of OXYS and Wistar (control) rats, genes of a neurotrophin signaling pathway with different mRNA levels in the period prior to the development of AD-like pathology in OXYS rats (20 days) and in the period of its active manifestation (5 months) and progression (18 months) were identified. The most significant changes in mRNA levels in the cortex of OXYS rats occurred in the period from 5 to 18 months of age. These genes were associated with neurogenesis, neuronal differentiation, synaptic plasticity, and immune response. The results were compared to changes in the levels of brain-derived neurotrophic factor (BDNF), its receptors TrkB and p75NTR, as well as with patterns of their colocalization, which reveal the balance of proneurotrophins and mature neurotrophins and their receptors. We found that alterations in neurotrophic balance indicating increased apoptosis precede the development of AD-like pathology in OXYS rats. Manifestation of AD-like pathology occurs against a background of activation of compensatory and regenerative processes including increased neurotrophic supplementation. Active progression of AD-like pathology in OXYS rats is accompanied by the suppression of activity of the neurotrophin system. Thus, the results confirm the importance of the neurotrophin system as a potential target for development of new approaches to slow age-related alterations in brain and AD development.
Subject(s)
Alzheimer Disease/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Cerebral Cortex/metabolism , Gene Expression Regulation , Receptor, trkB/biosynthesis , Receptors, Nerve Growth Factor/biosynthesis , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Animals , Brain-Derived Neurotrophic Factor/genetics , Cerebral Cortex/pathology , Disease Models, Animal , Male , Nerve Tissue Proteins , Rats , Rats, Wistar , Receptor, trkB/genetics , Receptors, Growth Factor , Receptors, Nerve Growth Factor/geneticsABSTRACT
The mitochondria-targeted antioxidant SkQ1 is a novel drug thought to retard development of age-related diseases. It has been shown that SkQ1 reduces clinical signs of retinopathy in senescence-accelerated OXYS rats, which are a known animal model of human age-related macular degeneration (AMD). The aim of this work was to test whether SkQ1 affects transcriptional activity of AhR (aryl hydrocarbon receptor) and Nrf2 (nuclear factor erythroid 2-related factor 2), which are considered as AMD-associated genes in the retina of OXYS and Wistar rats. Our results showed that only AhR and AhR-dependent genes were sensitive to SkQ1. Dietary supplementation with SkQ1 decreased the AhR mRNA level in both OXYS and Wistar rats. At baseline, the retinal Cyp1a1 mRNA level was lower in OXYS rats. SkQ1 supplementation decreased the Cyp1a1 mRNA level in Wistar rats, but this level remained unchanged in OXYS rats. Baseline Cyp1a2 and Cyp1b1 mRNA expression was stronger in OXYS than in Wistar rats. In the OXYS strain, Cyp1a2 and Cyp1b1 mRNA levels decreased as a result of SkQ1 supplementation. These data suggest that the Cyp1a2 and Cyp1b1 enzymes are involved in the pathogenesis of AMD-like retinopathy of OXYS rats and are possible therapeutic targets of SkQ1.
