Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats
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ORIGINAL ARTICLE
Aging exacerbates impairments of cerebral blood flow autoregulation and cognition in diabetic rats Shaoxun Wang & Wenshan Lv & Huawei Zhang & Yedan Liu & Longyang Li & Joshua R. Jefferson & Ya Guo & Man Li & Wenjun Gao & Xing Fang & Ian A. Paul & Grazyna Rajkowska & James P. Shaffery & Thomas H. Mosley & Xinlin Hu & Ruen Liu & Yangang Wang & Hongwei Yu & Richard J. Roman & Fan Fan
Received: 14 April 2020 / Accepted: 8 July 2020 # American Aging Association 2020
Abstract Diabetes mellitus (DM) is a leading risk factor for aging-related dementia; however, the underlying mechanisms are not well understood. The present study, utilizing a non-obese T2DN diabetic model, S. Wang : W. Lv : H. Zhang : Y. Liu : L. Li : J. R. Jefferson : Y. Guo : M. Li : W. Gao : X. Fang : R. J. Roman : F. Fan (*) Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA e-mail: [email protected] W. Lv : X. Hu : Y. Wang Department of Endocrinology and Metabolic, The Affiliated Hospital of Qingdao University, Qingdao 266003 Shandong, China I. A. Paul : G. Rajkowska : J. P. Shaffery Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS 39216, USA T. H. Mosley Department of Neurology, University of Mississippi Medical Center, Jackson, MS 39216, USA T. H. Mosley Department of Medicine (Geriatrics), University of Mississippi Medical Center, Jackson, MS 39216, USA R. Liu Department of Neurosurgery, Peking University People’s Hospital, Beijing 100044, China H. Yu Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
demonstrates that the myogenic response of the middle cerebral artery (MCA) and parenchymal arteriole (PA) and autoregulation of cerebral blood flow (CBF) in the surface and deep cortex were impaired at both young and old ages. The impaired CBF autoregulation was more severe in old than young DM rats, and in the deep than the surface cortex. The myogenic tone of the MCA was enhanced at perfusion pressure in the range of 40– 100 mmHg in young DM rats but was reduced at 140– 180 mmHg in old DM rats. No change of the myogenic tone of the PA was observed in young DM rats, whereas it was significantly reduced at 30–60 mmHg in old DM rats. Old DM rats had enhanced blood-brain barrier (BBB) leakage and neurodegeneration, reduced vascular density, tight junction, and pericyte coverage on cerebral capillaries in the CA3 region in the hippocampus. Additionally, DM rats displayed impaired functional hyperemia and spatial learning and short- and longterm memory at both young and old ages. Old DM rats had impaired non-spatial short-term memory. These results revealed that impaired CBF autoregulation and enhanced BBB leakage plays an essential role in the pathogenesis of age- and diabetes-related dementia. These findings will lay the foundations for the discovery of anti-diabetic therapies targeting restoring CBF autoregulation to prevent the onset and progression of dementia in elderly
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