Abstract
BackgroundCerebrovascular 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.ResultsWe 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.ConclusionsChanges 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.
Highlights
Cerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD): the most common cause of dementia in the elderly
In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found 3 pathways (p < 0.05) associated with blood vessel processes in OXYS rats: the vascular smooth muscle contraction pathway was upregulated in OXYS rats at the age of 20 days and 5 months; the vascular endothelial growth factor (VEGF) signaling pathway was upregulated at the age of 20 days and downregulated at the age of 18 months; the hematopoietic cell lineage pathway was downregulated at the age of 5 and 18 months (Additional file 2)
Analysis of the gene networks in 20-day-old and 5- and 18-monthold animals revealed that the common genes probably play a significant role in the regulation of blood vessel processes in the hippocampus of OXYS rats during development of AD-like pathology: Nos1, P2rx4, Pla2g6, and Bdkrb2. These results indicate that in OXYS rats, the development of AD signs is preceded by changes in the expression of hippocampal genes involved in cerebrovascular processes; these changes increased with the progression of disease pathology
Summary
Cerebrovascular dysfunction plays a critical role in the pathogenesis of Alzheimer’s disease (AD): the most common cause of dementia in the elderly. Vascular dysfunction is a universal feature of aging that contributes to the cognitive decline and neurodegeneration observed in Alzheimer’s disease (AD): the most common cause of dementia in the elderly [1, 2]. AD is characterized by a gradual decline in memory and cognition that correlate with synaptic dysfunction and neuronal loss It was suggested over 30 years ago that vascular defects present in AD may be important for the development of the disease [3]. It is clear that microvascular deficits diminish cerebral blood flow and, the brain’s supply of oxygen, energy, substrates, and nutrients Such deficits impair the clearance of neurotoxic molecules, such as amyloid β (Aβ), which are released into the brain interstitial fluid and accumulate in the parenchyma and vessel walls. These changes include alterations in density and morphology of cerebral microvasculature, increased endothelial pinocytosis, a decrease in mitochondrial content, accumulation of collagen and perlecans in the basement membrane, loss of tight junctions and/or adherens junctions, and a blood-brain barrier breakdown with leakage of blood-borne molecules [4, 5]
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