title: Blood-brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment.
abstract: BACKGROUND
  Functional loss of blood-brain barrier (BBB) is suggested to be pivotal to pathogenesis and pathology of vascular-based neurodegenerative disorders such as Alzheimer's disease. We recently reported in wild-type mice maintained on standard diets, progressive deterioration of capillary function with aging concomitant with heightened neuroinflammation. However, the mice used in this study were relatively young (12 months of age) and potential mechanisms for loss of capillary integrity were not investigated per se. The current study therefore extended the previous finding to investigate the effect of aging on BBB integrity in aged mice at 24 months and its potential underlying molecular mechanisms.
  
  
  RESULTS
  Immunomicroscopy analyses confirmed significantly increased capillary permeability with heightened neuroinflammation in naturally aged 24-month old mice compared to young control at 3 months of age. Aged mice showed significant attenuation in the expression of BBB tight junction proteins, occludin-1 and to lesser extent ZO-1 compared to young mice. In addition, TNF-α in cerebral endothelial cells of aged mice was significantly elevated compared to controls and this was associated with heightened peripheral inflammation. The expression of ICAM-1 and VCAM-1 remained unelevated, and no sign of leukocyte recruitment was observed in aged mice.
  
  
  CONCLUSIONS
  The BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Mina
authors.initials: M
authors.lastname: Elahy
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Connie
authors.initials: C
authors.lastname: Jackaman
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: John Cl
authors.initials: JC
authors.lastname: Mamo
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Virginie
authors.initials: V
authors.lastname: Lam
authors.affiliation: School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Satvinder S
authors.initials: SS
authors.lastname: Dhaliwal
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Corey
authors.initials: C
authors.lastname: Giles
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Biomedical Sciences, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Delia
authors.initials: D
authors.lastname: Nelson
authors.affiliation: CHIRI Institute for Ageing and Chronic Disease, Curtin University, Bentley, 6102 WA Australia ; School of Public Health, Faculty of Health Sciences, Curtin University, Bentley, 6102 WA Australia.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Takechi
keywords: Aging; Blood–brain barrier; Inflammation; Leukocyte infiltration; Neurodegenerative disorder; Neuroinflammation; Tight junction complex