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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.

Elahy M, Jackaman C, Mamo JC, Lam V, Dhaliwal SS, Giles C, Nelson D, Takechi R - Immun Ageing (2015)

Bottom Line: 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.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 BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.

View Article: PubMed Central - PubMed

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.

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.

Conclusion: The BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.

No MeSH data available.


Related in: MedlinePlus

Blood–brain barrier integrity and neuroinflammation. (A) The integrity of BBB was assessed by measuring the blood-to-brain extravasation of IgG with semi-quantitative confocal microscopy in the cortex (CTX) and hippocampal formation (HPF) of 3 months old young mice and 24 months old aged mice. The voxel intensity of protein of interest is expressed as per volume unit. Asterisks indicate statistical significance assessed with two-tailed t-test (p < 0.05, n = 6). Representative immunomicrographs are also shown (green = IgG, blue = DAPI, scale bar = 20 μm). (B) The astroglial activation, neuronal ER stress and inflammation were assessed by measuring the expression of GFAP, GRP78 and COX-2 respectively. Representative immunomicrographs are shown (yellow = GFAP, red = GRP78, magenta = COX-2, blue = DAPI, scale bar = 50 μm).
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Fig1: Blood–brain barrier integrity and neuroinflammation. (A) The integrity of BBB was assessed by measuring the blood-to-brain extravasation of IgG with semi-quantitative confocal microscopy in the cortex (CTX) and hippocampal formation (HPF) of 3 months old young mice and 24 months old aged mice. The voxel intensity of protein of interest is expressed as per volume unit. Asterisks indicate statistical significance assessed with two-tailed t-test (p < 0.05, n = 6). Representative immunomicrographs are also shown (green = IgG, blue = DAPI, scale bar = 20 μm). (B) The astroglial activation, neuronal ER stress and inflammation were assessed by measuring the expression of GFAP, GRP78 and COX-2 respectively. Representative immunomicrographs are shown (yellow = GFAP, red = GRP78, magenta = COX-2, blue = DAPI, scale bar = 50 μm).

Mentions: The mice aged to 24 months were otherwise healthy and had no adverse event recorded. The extravasation of circulating IgG into cerebral parenchyme was significantly increased in the cortex and hippocampal formation of aged mice compared to young control mice (Figure 1A). Significantly elevated neurovascular inflammation and neuronal stress were also indicated with increased expression of GFAP, GRP78 and COX-2 in 24 months old mice (Figure 1B).Figure 1


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

Elahy M, Jackaman C, Mamo JC, Lam V, Dhaliwal SS, Giles C, Nelson D, Takechi R - Immun Ageing (2015)

Blood–brain barrier integrity and neuroinflammation. (A) The integrity of BBB was assessed by measuring the blood-to-brain extravasation of IgG with semi-quantitative confocal microscopy in the cortex (CTX) and hippocampal formation (HPF) of 3 months old young mice and 24 months old aged mice. The voxel intensity of protein of interest is expressed as per volume unit. Asterisks indicate statistical significance assessed with two-tailed t-test (p < 0.05, n = 6). Representative immunomicrographs are also shown (green = IgG, blue = DAPI, scale bar = 20 μm). (B) The astroglial activation, neuronal ER stress and inflammation were assessed by measuring the expression of GFAP, GRP78 and COX-2 respectively. Representative immunomicrographs are shown (yellow = GFAP, red = GRP78, magenta = COX-2, blue = DAPI, scale bar = 50 μm).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4362825&req=5

Fig1: Blood–brain barrier integrity and neuroinflammation. (A) The integrity of BBB was assessed by measuring the blood-to-brain extravasation of IgG with semi-quantitative confocal microscopy in the cortex (CTX) and hippocampal formation (HPF) of 3 months old young mice and 24 months old aged mice. The voxel intensity of protein of interest is expressed as per volume unit. Asterisks indicate statistical significance assessed with two-tailed t-test (p < 0.05, n = 6). Representative immunomicrographs are also shown (green = IgG, blue = DAPI, scale bar = 20 μm). (B) The astroglial activation, neuronal ER stress and inflammation were assessed by measuring the expression of GFAP, GRP78 and COX-2 respectively. Representative immunomicrographs are shown (yellow = GFAP, red = GRP78, magenta = COX-2, blue = DAPI, scale bar = 50 μm).
Mentions: The mice aged to 24 months were otherwise healthy and had no adverse event recorded. The extravasation of circulating IgG into cerebral parenchyme was significantly increased in the cortex and hippocampal formation of aged mice compared to young control mice (Figure 1A). Significantly elevated neurovascular inflammation and neuronal stress were also indicated with increased expression of GFAP, GRP78 and COX-2 in 24 months old mice (Figure 1B).Figure 1

Bottom Line: 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.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 BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.

View Article: PubMed Central - PubMed

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.

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.

Conclusion: The BBB breakdown that occurs during ordinary aging is associated with inflammation and disruption of tight junction complex assembly but not through leukocyte trafficking.

No MeSH data available.


Related in: MedlinePlus