Senescence-accelerated OXYS rats are an experimental model of accelerated aging that was established from Wistar stock via selection for susceptibility to cataractogenic effects of a galactose-rich...

Melatonin is a multifunctional molecule and plays a crucial role in the regulation of circadian rhythms. The role of melatonin in the protection of the central nervous system is well documented. Therefore, melatonin was proposed as a possible therape

Mitochondrial aberrations are observed in human Alzheimer's disease (AD) and in medical conditions that increase the risk of this disorder, suggesting that mitochondrial dysfunction may contribute to pathophysiology of AD. Here, using OXYS rats that simulate key characteristics of sporadic AD, we set out to determine the role of mitochondria in the pathophysiology of this disorder. OXYS rats were treated with a mitochondria-targeted antioxidant SkQ1 from age 12 to 18 months, that is, during active progression of AD-like pathology in these animals. Dietary supplementation with SkQ1 caused this compound to accumulate in various brain regions, and it was localized mostly to neuronal mitochondria. Via improvement of structural and functional state of mitochondria, treatment with SkQ1 alleviated the structural neurodegenerative alterations, prevented the neuronal loss and synaptic damage, increased the levels of synaptic proteins, enhanced neurotrophic supply, and decreased amyloid-β1-42 protein levels and tau hyperphosphorylation in the hippocampus of OXYS rats, resulting in improvement of the learning ability and memory. Collectively, these data support that mitochondrial dysfunction may play a key role in the pathophysiology of AD and that therapies with target mitochondria are potent to normalize a wide range of cellular signaling processes and therefore slow the progression of AD.

Cerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD): the most common cause of dementia in the elderly. The involvement of neurovasculature disorders in the progression of AD is now increasingly appreciated, but whether they represent initial factors or late-stage pathological changes during the disease is unclear. Using senescence-accelerated OXYS rats, which simulate key characteristics of sporadic AD, we evaluated contributions of cerebrovascular alterations to the disease development. At preclinical, early, and advanced stages of AD-like pathology, in the hippocampus of OXYS and Wistar (control) rats, we evaluated (i) the blood vessel state by histological and electron-microscopic analyses; (ii) differences in gene expression according to RNA sequencing (RNA-Seq) to identify the metabolic processes and pathways associated with blood vessel function; (iii) the amount of vascular endothelial growth factor (VEGF) by western blot and immunohistochemical analysis. We observed a loss of hippocampal blood vessel density and ultrastructural changes of those blood vessels in OXYS rats at the early stage of AD-like pathology. There were significant alterations in the vessels and downregulation of VEGF with an increased amount of amyloid β1–42 there at the advanced stage of the disease. According to RNA-Seq data analysis, major alterations in cerebrovascular processes of OXYS rats were associated with blood vessel development, circulatory system processes, the VEGF signaling pathway, and vascular smooth muscle contraction. At preclinical and early stages of the AD-like pathology, these processes were upregulated and then downregulated with age. At the advanced stage in OXYS rats, differentially expressed genes (DEGs) were associated with downregulation of cerebrovascular function as compared to Wistar rats. Among the 46 DEGs at the preclinical stage of the disease, 28 DEGs at the early stage, and among 85 DEGs at the advanced stage, using functional analysis and gene network construction, we identified genes (Nos1, P2rx4, Pla2g6, and Bdkrb2) probably playing a significant role in the development of cerebrovascular dysfunction in OXYS rats. Changes in expression of the genes functionally associated with cerebrovascular processes already in the early period of life may contribute to the development of AD-like pathology in OXYS rats.