Association of cerebrovascular dysfunction with the development of Alzheimer’s disease-like pathology in OXYS rats

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.Electronic supplementary materialThe online version of this article (10.1186/s12864-018-4480-9) contains supplementary material, which is available to authorized users.

The Bdkrb2 Gene Family Provides a Novel View of Viviparity Adaptation in Sebastes schlegelii

“…Bdkrb2 was one of genes related to cerebrovascular dysfunction with the development of Alzheimer's disease-like pathology in OXYS rats. Its expression was found to be reduced at 20-day-old and 18-month-old, and was increased at 5-month-old in OXYS rats [35]. However, the underlying mechanisms need further research.…”

Identification of blood-activating components from Xueshuan Xinmaining Tablet based on the spectrum–effect relationship and network pharmacology analysis

“…[65][66][67] TNF (tumor necrosis factor), an inammatory cytokine (including TNF-a and TNF-b), mainly secreted by macrophages and T lymphocytes during acute inammation, acts as an inammatory mediator by preventing endotoxin shock, and has anti-tumor effects and anti-infective effects by inhibiting viral replication and killing virus-infected cells/tumor cells. 68 VEGFA, a key vascular endothelial growth factor to promote angiogenesis and axonal regeneration, 69 promotes endothelial cell proliferation, induces cell migration, induces permeabilization of blood vessels, and suppresses apoptosis. 70 Although further experimental validations of the network pharmacology prediction are required in future studies, utilizing network pharmacology in TCM research is an efficient method to elucidate how multiple components interact with multiple targets, which is consistent with the theory of TCM synergy.…”

Treating Dementia Early: Limiting Cellular Damage in Brain Tissue

“…Cognitive impairment late in life is associated with two dominant diseases in humans, i.e., Alzheimer's disease and small vessel cerebrovascular disease, both causing brain atrophy years before clinical symptoms are detected. In fact, vascular brain lesions are very common in people over 70 years old, and recent reviews (e.g., [1,2] for background information) provide much evidence that a large proportion of dementia cases may be attributable to cerebrovascular disease (see also [3,4] and below). These vascular lesions include alterations in density and morphology of cerebral microvasculature, and a blood-brain barrier (BBB) breakdown with leakage of bloodborne molecules (see [4] for recent animal data, and a description of human data contained in citations 4-6 therein).…”

“…In fact, vascular brain lesions are very common in people over 70 years old, and recent reviews (e.g., [1,2] for background information) provide much evidence that a large proportion of dementia cases may be attributable to cerebrovascular disease (see also [3,4] and below). These vascular lesions include alterations in density and morphology of cerebral microvasculature, and a blood-brain barrier (BBB) breakdown with leakage of bloodborne molecules (see [4] for recent animal data, and a description of human data contained in citations 4-6 therein). Accordingly, vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease, and is a frequent co-morbidity in the Alzheimer's patient (e.g., [5,6]; cf.…”

“…It is no surprise, therefore, that multiple epidemiological studies have shown a marked overlap among risk factors for small vessel cerebrovascular disease and lateonset Alzheimer's disease. Furthermore, growing data from brain imaging studies and various animal models suggest that cerebrovascular dysfunction may well preceed cognitive impairment and the onset of neurodegenerative changes in Alzheimer's disease [2,4].…”