Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease. It produces atrophic changes in the brain, which cause dementia. The incidence of AD is increasing with increasing life expectancy and gradual aging of the population in developed countries. There are no effective prophylactic interventions because of insufficient understanding of the AD pathogenesis and the absence of adequate experimental models. Recently, we showed that senescence-accelerated OXYS rats represent a promising model of AD; in these rats, accelerated aging of the brain is accompanied by the typical signs of AD: degenerative alterations and death of neurons, a decrease in synaptic density, mitochondrial dysfunction, hyperphosphorylation of the tau protein, an increased level of amyloid β (Aβ1–42), and the formation of amyloid plaques. To elucidate how these signs develop, we used a nextgeneration RNA sequencing technique (RNA-Seq) to study the prefrontal-cortex transcriptome of OXYS rats during the manifestation of AD signs (at an age of 5 months) and during their active progression (at an age of 18 months), using age-matched Wistar rats (parental strain) as controls. At the age of 5 months, there were significant differences between OXYS and Wistar rats (p < 0.01) in the mRNA expression of more than 900 genes (> 2000 genes at the age of 18 months) in the prefrontal cortex. Most of these genes were related to neuronal plasticity, protein phosphorylation, Са2+ homeostasis, hypoxia, immune processes, and apoptosis. Between the ages of 5 and 18 months, there were changes in the expression of 499 genes in Wistar rats and changes in the expression of 5500 genes in OXYS rats. Only 333 genes were common between these sets. This finding points to differences in the mechanisms and rates of age-related changes in the brain between normal aging and the period of development of AD-specific neurodegenerative processes.
Highlights
Changes in the transcriptome of the prefrontal cortex of OXYS rats as the signs of Alzheimer’s disease development
The incidence of Alzheimer’s disease (AD) is increasing with increasing life expectancy and gradual aging of the population in developed countries
We showed that senescence-accelerated OXYS rats represent a promising model of AD; in these rats, accelerated aging of the brain is accompanied by the typical signs of AD: degenerative alterations and death of neurons, a decrease in synaptic density, mitochondrial dysfunction, hyperphosphorylation of the tau protein, an increased level of amyloid β (Aβ1–42), and the formation of amyloid plaques
Summary
Болезнь Альцгеймера (БА) – самое распространенное нейродегенеративное заболевание, которое становится причиной деменции на фоне атрофических изменений мозга. Анализ данных секвенирования транскриптома (RNA-seq) Установлено, что при заданной глубине секвенирования в префронтальной коре крыс OXYS и Вистар, согласно методу DESeq, экспрессируется около 15 200 генов. Что количество генов, экспрессия которых в префронтальной коре мозга крыс OXYS и Вистар различна (при уровне значимости р < 0,01), с 5 до 18 мес. Экспрессия которых с возрастом изменилась однонаправленно в префронтальной коре крыс обеих линий, показало, что у 191 из них она возросла, а у 142 – снизилась В целом такие результаты свидетельствуют о различиях в механизмах и скорости изменений в префронтальной коре при нормальном темпе старения мозга у крыс Вистар и при развитии характерных для БА нейродегенеративных процессов у крыс OXYS. 3 представлены основные биологические процессы (термины генных онтологий – Gene Ontology), для которых выявлены значимые изменения экспрессии генов в префронтальной коре с возрастом у крыс OXYS и Вистар.
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