Blood–brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment

Elahy, Mina; Jackaman, Connie; Mamo, John; Lam, Virginie; Dhaliwal, Satvinder S.; Giles, Corey; Nelson, Delia J.; Takechi, Ryusuke

doi:10.1186/s12979-015-0029-9

Cited by 237 publications

(196 citation statements)

References 43 publications

(45 reference statements)

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“…Several inflammatory mediators, such as the cytokines tumor necrosis factor (TFN)-α, interleukin (IL)-1β, IL-6, and IL-17A [32] as well as molecules such as C-reactive protein (CRP), cyclooxygenase (COX)-2, and endothelin (ET)-1 [4] are released during sleep loss and are able to modify tight junction protein expression both in in vitro and in in vivo experiments (for a review see [33, 34]). In addition, the decrease of ZO-1 and occludin might be associated to subtle permeability changes related to peripheral inflammation like that occurring in naturally aged rodents [35]. …”

Section: Discussionmentioning

confidence: 99%

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

et al. 2016

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Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and increased blood-brain barrier permeability.

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Section: Discussionmentioning

confidence: 99%

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

et al. 2016

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“…Astrocytes express TJ proteins and densely and tightly surround mature neurons to protect them from blood-derived neurotoxic substances. 71 The main changes at the BBB during physiological aging are presented in Table 1.…”

Section: Changes In the Bbb With Physiological Agingmentioning

confidence: 99%

“…79,92 Pericytes are uniquely positioned within the NVU between ECs of brain capillaries, astrocytes and neurons. Winkler et al have reviewed the concept of the NVU and neurovascular functions of CNS pericytes, discussing vascular contributions to Alzheimer's disease and new roles of pericytes in the pathogenesis of 72 Hicks et al 44 Burns et al 49 Hunziker et al 72 Burns et al 49,50 Grammas et al 18 Tight junctions Expression of tight junction proteins: decreased Elahy et al, 71 Enciu et al 73 Basal lamina Thickness of basement membrane: Increased Concentration of collagen IV and argin: Increased Concentration of laminin: decreased Candiello et al, 29 Ravens 74 Candiello et al 29 Candiello et al 29 …”

Section: Bbb In Alzheimer's Diseasementioning

confidence: 99%

Age-associated physiological and pathological changes at the blood–brain barrier: A review

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2016

J Cereb Blood Flow Metab

344

260

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The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of aged populations. The morphological and biochemical changes in the aging brain are the subjects of many extended research projects worldwide for a long time. However, the crucial role of the blood-brain barrier (BBB) impairment and disruption in the pathological processes in age-associated neurodegenerative disorders received special attention just for a few years. This article gives an overview on the major elements of the blood-brain barrier and its supporting mechanisms and also on their alterations during development, physiological aging process and age-associated neurodegenerative disorders (Alzheimer's disease, multiple sclerosis, Parkinson's disease, pharmacoresistant epilepsy). Besides the morphological alterations of the cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal elements) of the BBB and neurovascular unit, the changes of the barrier at molecular level (tight junction proteins, adheres junction proteins, membrane transporters, basal lamina, extracellular matrix) are also summarized. The recognition of new players and initiators of the process of neurodegeneration at the level of the BBB may offer new avenues for novel therapeutic approaches for the treatment of numerous chronic neurodegenerative disorders currently without effective medication. KeywordsAging, blood-brain barrier, endothelial cells, neurodegenerative disorders, transport systems Structure of the blood-brain barrier (BBB)Homeostasis of the extracellular microenvironment in the neural tissue of the brain as well as its protection against neurotoxic compounds and variations in the composition of the blood are important for normal function of the neurons. It is warranted by a structure formed between blood and brain, which is therefore called the BBB.1 Clear evidence for the existence of this permeability barrier in the brain emerged in 1909 with the demonstration by Edwin Goldman (a South African-German) that a dye injected into the blood stream of a rat stained the whole body -except for the brain and spinal cord. The opposite was also true: injection of the dye into the cerebral ventricles stained the brain and spinal cord but not the rest of the body. 2,3 This occurs because most organs of the body are perfused by capillaries lined with endothelial cells (ECs) that have small pores (fenestrations) to allow for the rapid movement of small molecules into the organ interstitial fluid from the circulation. However, the capillary endothelium of the brain and spinal cord lack these pores because the ECs of brain capillary are connected to each other by continuous tight junctions (TJs), produced by the interaction of several transmembrane proteins that project into and seal the paracellular pathway.3-5 The interaction of these junctional proteins effectively blocks the free diffusion of

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“…Moreover, attenuated expression of endothelial junctional proteins may result in greater transendothelial rates of molecular transport. This phenomenon has been described in neurological disorders [24] and also in brain capillaries of aged rodent models [25, 26]. The latter was reported to be exacerbated by high fat feeding with diets enriched in saturated fats or cholesterol [27].…”

Section: Introductionmentioning

confidence: 91%

The Effects of Long-Term Saturated Fat Enriched Diets on the Brain Lipidome

et al. 2016

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The brain is highly enriched in lipids, where they influence neurotransmission, synaptic plasticity and inflammation. Non-pathological modulation of the brain lipidome has not been previously reported and few studies have investigated the interplay between plasma lipid homeostasis relative to cerebral lipids. This study explored whether changes in plasma lipids induced by chronic consumption of a well-tolerated diet enriched in saturated fatty acids (SFA) was associated with parallel changes in cerebral lipid homeostasis. Male C57Bl/6 mice were fed regular chow or the SFA diet for six months. Plasma, hippocampus (HPF) and cerebral cortex (CTX) lipids were analysed by LC-ESI-MS/MS. A total of 348 lipid species were determined, comprising 25 lipid classes. The general abundance of HPF and CTX lipids was comparable in SFA fed mice versus controls, despite substantial differences in plasma lipid-class abundance. However, significant differences in 50 specific lipid species were identified as a consequence of SFA treatment, restricted to phosphatidylcholine (PC), phosphatidylethanolamine (PE), alkyl-PC, alkenyl-PC, alkyl-PE, alkenyl-PE, cholesterol ester (CE), diacylglycerol (DG), phosphatidylinositol (PI) and phosphatidylserine (PS) classes. Partial least squares regression of the HPF/CTX lipidome versus plasma lipidome revealed the plasma lipidome could account for a substantial proportion of variation. The findings demonstrate that cerebral abundance of specific lipid species is strongly associated with plasma lipid homeostasis.

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Blood–brain barrier dysfunction developed during normal aging is associated with inflammation and loss of tight junctions but not with leukocyte recruitment

Cited by 237 publications

References 43 publications

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

Age-associated physiological and pathological changes at the blood–brain barrier: A review

The Effects of Long-Term Saturated Fat Enriched Diets on the Brain Lipidome

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