TY - JOUR

T1 - Association of cerebrovascular dysfunction with the development of Alzheimer's disease-like pathology in OXYS rats

AU - Stefanova, Natalia A.

AU - Maksimova, Kseniya Yi

AU - Rudnitskaya, Ekaterina A.

AU - Muraleva, Natalia A.

AU - Kolosova, Nataliya G.

N1 - Publisher Copyright: © 2018 The Author(s).

PY - 2018/2/9

Y1 - 2018/2/9

N2 - Background: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Results: 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. Conclusions: 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.

KW - Alzheimer's disease

KW - Cerebrovascular dysfunction

KW - OXYS rats

KW - RNA sequencing

KW - Aging/genetics

KW - Species Specificity

KW - Alzheimer Disease/genetics

KW - Molecular Sequence Annotation

KW - Rats

KW - Gene Expression Profiling

KW - Gene Regulatory Networks

KW - Vascular Endothelial Growth Factor A/metabolism

KW - Hippocampus/blood supply

KW - Blood Vessels/physiopathology

KW - Animals

KW - Peptide Fragments/metabolism

KW - Amyloid beta-Peptides/metabolism

KW - COGNITIVE IMPAIRMENT

KW - NEURODEGENERATION

KW - NITRIC-OXIDE

KW - BRAIN

KW - ENDOTHELIAL GROWTH-FACTOR

KW - MECHANISMS

KW - CORTEX

KW - ACCUMULATION

KW - CEREBRAL-BLOOD-FLOW

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85041865475&partnerID=8YFLogxK

U2 - 10.1186/s12864-018-4480-9

DO - 10.1186/s12864-018-4480-9

M3 - Article

C2 - 29504901

AN - SCOPUS:85041865475

VL - 19

SP - 75

JO - BMC Genomics

JF - BMC Genomics

SN - 1471-2164

IS - Suppl 3

M1 - 75

ER -