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Blood-brain barrier impairment in an animal model of MPS III B.

Garbuzova-Davis S, Louis MK, Haller EM, Derasari HM, Rawls AE, Sanberg PR - PLoS ONE (2011)

Bottom Line: Sanfilippo syndrome type B (MPS III B) is caused by a deficiency of α-N-acetylglucosaminidase enzyme, leading to accumulation of heparan sulfate within lysosomes and eventual progressive cerebral and systemic multiple organ abnormalities.BBB dysfunction in this devastating disorder could contribute to neuropathological disease manifestations.Major findings of our study were: (1) endothelial cell damage in capillary ultrastructure, compromising the BBB and resulting in vascular leakage, (2) formation of numerous large vacuoles in endothelial cells and perivascular cells (pericytes and perivascular macrophages) in the large majority of vessels, (3) edematous space around microvessels, (4) microaneurysm adjacent to a ruptured endothelium, (6) Evans Blue and albumin microvascular leakage in various brain structures, (7) GM3 ganglioside accumulation in endothelium of the brain microvasculature.

View Article: PubMed Central - PubMed

Affiliation: College of Medicine, Center of Excellence for Aging & Brain Repair, University of South Florida, Tampa, Florida, United States of America. sgarbuzo@health.usf.edu

ABSTRACT

Background: Sanfilippo syndrome type B (MPS III B) is caused by a deficiency of α-N-acetylglucosaminidase enzyme, leading to accumulation of heparan sulfate within lysosomes and eventual progressive cerebral and systemic multiple organ abnormalities. However, little is known about the competence of the blood-brain barrier (BBB) in MPS III B. BBB dysfunction in this devastating disorder could contribute to neuropathological disease manifestations.

Methodology/principal findings: In the present study, we investigated structural (electron microscope) and functional (vascular leakage) integrity of the BBB in a mouse model of MPS III B at different stages of disease, focusing on brain structures known to experience neuropathological changes. Major findings of our study were: (1) endothelial cell damage in capillary ultrastructure, compromising the BBB and resulting in vascular leakage, (2) formation of numerous large vacuoles in endothelial cells and perivascular cells (pericytes and perivascular macrophages) in the large majority of vessels, (3) edematous space around microvessels, (4) microaneurysm adjacent to a ruptured endothelium, (6) Evans Blue and albumin microvascular leakage in various brain structures, (7) GM3 ganglioside accumulation in endothelium of the brain microvasculature.

Conclusions/significance: These new findings of BBB structural and function impairment in MPS III B mice even at early disease stage may have implications for disease pathogenesis and should be considered in current and future development of treatments for MPS III B.

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Evans Blue (EB) fluorescence in the brains of Naglu mice.In the brain, EB can be clearly detected within the blood vessels (A, B, C, red, arrowheads) in the control C57 BL/6J mouse at 12 months of age. In Naglu mice, vascular leakage of EB (red, arrows) is visible in various brain structures (D, E, F) at early (3 months of age), (J, H, I) at late (6 months of age), and (J, K, L) at end stage of disease (10 months of age). Significant EB diffusion into the brain parenchyma from many blood vessels can be detected in end-stage Naglu mouse (10–12 months of age). Cx – cerebral cortex, Hip – hippocampus, Crb – cerebellum. Scale bar in A through L is 25 µm.
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pone-0016601-g005: Evans Blue (EB) fluorescence in the brains of Naglu mice.In the brain, EB can be clearly detected within the blood vessels (A, B, C, red, arrowheads) in the control C57 BL/6J mouse at 12 months of age. In Naglu mice, vascular leakage of EB (red, arrows) is visible in various brain structures (D, E, F) at early (3 months of age), (J, H, I) at late (6 months of age), and (J, K, L) at end stage of disease (10 months of age). Significant EB diffusion into the brain parenchyma from many blood vessels can be detected in end-stage Naglu mouse (10–12 months of age). Cx – cerebral cortex, Hip – hippocampus, Crb – cerebellum. Scale bar in A through L is 25 µm.

Mentions: The functional competence of the BBB in Naglu mice at different stages of disease was determined by examining vascular leakage of EB, 961 Da, and albumin, 68 kD. In control wild type mice at 3, 6 or 10-12 months of age, EB (Figure 5, A–C) and albumin (Figure 6, A–C) were clearly detected within the blood vessels of the brain. Vascular leakage of EB and albumin was observed in early (3 months of age) (Figures 5 and 6, D–F) and late symptomatic Naglu mice (6 months of age) (Figures 5 and 6, G, H, I) in various brain structures. Significant EB and albumin diffusion into the parenchyma of the brain from multiple blood vessels was detected in both male and female end stage Naglu mice (10–12 months of age) (Figures 5 and 6, J–L). Although the entire sectioned brain was analyzed for vascular leakage, the majority of blood vessel leakage was detected in the cerebellar lobules (6–9Cb), cerebral cortex (M2), hippocampus (CA1, CA2), and midbrain of mutant mice at all disease stages (Table 1). Although both EB and albumin extravasation abnormalities were commonly found in the same microvessels (Figures 5 and 6, E, K, L), some capillaries showed only EB leakage. Interestingly, neither EB nor albumin leakage was indicated in the olfactory bulb. Thus, vascular leakage of EB and albumin was detected in Naglu mice not only at late stage of disease but also concurrent with early disease symptoms.


Blood-brain barrier impairment in an animal model of MPS III B.

Garbuzova-Davis S, Louis MK, Haller EM, Derasari HM, Rawls AE, Sanberg PR - PLoS ONE (2011)

Evans Blue (EB) fluorescence in the brains of Naglu mice.In the brain, EB can be clearly detected within the blood vessels (A, B, C, red, arrowheads) in the control C57 BL/6J mouse at 12 months of age. In Naglu mice, vascular leakage of EB (red, arrows) is visible in various brain structures (D, E, F) at early (3 months of age), (J, H, I) at late (6 months of age), and (J, K, L) at end stage of disease (10 months of age). Significant EB diffusion into the brain parenchyma from many blood vessels can be detected in end-stage Naglu mouse (10–12 months of age). Cx – cerebral cortex, Hip – hippocampus, Crb – cerebellum. Scale bar in A through L is 25 µm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3049764&req=5

pone-0016601-g005: Evans Blue (EB) fluorescence in the brains of Naglu mice.In the brain, EB can be clearly detected within the blood vessels (A, B, C, red, arrowheads) in the control C57 BL/6J mouse at 12 months of age. In Naglu mice, vascular leakage of EB (red, arrows) is visible in various brain structures (D, E, F) at early (3 months of age), (J, H, I) at late (6 months of age), and (J, K, L) at end stage of disease (10 months of age). Significant EB diffusion into the brain parenchyma from many blood vessels can be detected in end-stage Naglu mouse (10–12 months of age). Cx – cerebral cortex, Hip – hippocampus, Crb – cerebellum. Scale bar in A through L is 25 µm.
Mentions: The functional competence of the BBB in Naglu mice at different stages of disease was determined by examining vascular leakage of EB, 961 Da, and albumin, 68 kD. In control wild type mice at 3, 6 or 10-12 months of age, EB (Figure 5, A–C) and albumin (Figure 6, A–C) were clearly detected within the blood vessels of the brain. Vascular leakage of EB and albumin was observed in early (3 months of age) (Figures 5 and 6, D–F) and late symptomatic Naglu mice (6 months of age) (Figures 5 and 6, G, H, I) in various brain structures. Significant EB and albumin diffusion into the parenchyma of the brain from multiple blood vessels was detected in both male and female end stage Naglu mice (10–12 months of age) (Figures 5 and 6, J–L). Although the entire sectioned brain was analyzed for vascular leakage, the majority of blood vessel leakage was detected in the cerebellar lobules (6–9Cb), cerebral cortex (M2), hippocampus (CA1, CA2), and midbrain of mutant mice at all disease stages (Table 1). Although both EB and albumin extravasation abnormalities were commonly found in the same microvessels (Figures 5 and 6, E, K, L), some capillaries showed only EB leakage. Interestingly, neither EB nor albumin leakage was indicated in the olfactory bulb. Thus, vascular leakage of EB and albumin was detected in Naglu mice not only at late stage of disease but also concurrent with early disease symptoms.

Bottom Line: Sanfilippo syndrome type B (MPS III B) is caused by a deficiency of α-N-acetylglucosaminidase enzyme, leading to accumulation of heparan sulfate within lysosomes and eventual progressive cerebral and systemic multiple organ abnormalities.BBB dysfunction in this devastating disorder could contribute to neuropathological disease manifestations.Major findings of our study were: (1) endothelial cell damage in capillary ultrastructure, compromising the BBB and resulting in vascular leakage, (2) formation of numerous large vacuoles in endothelial cells and perivascular cells (pericytes and perivascular macrophages) in the large majority of vessels, (3) edematous space around microvessels, (4) microaneurysm adjacent to a ruptured endothelium, (6) Evans Blue and albumin microvascular leakage in various brain structures, (7) GM3 ganglioside accumulation in endothelium of the brain microvasculature.

View Article: PubMed Central - PubMed

Affiliation: College of Medicine, Center of Excellence for Aging & Brain Repair, University of South Florida, Tampa, Florida, United States of America. sgarbuzo@health.usf.edu

ABSTRACT

Background: Sanfilippo syndrome type B (MPS III B) is caused by a deficiency of α-N-acetylglucosaminidase enzyme, leading to accumulation of heparan sulfate within lysosomes and eventual progressive cerebral and systemic multiple organ abnormalities. However, little is known about the competence of the blood-brain barrier (BBB) in MPS III B. BBB dysfunction in this devastating disorder could contribute to neuropathological disease manifestations.

Methodology/principal findings: In the present study, we investigated structural (electron microscope) and functional (vascular leakage) integrity of the BBB in a mouse model of MPS III B at different stages of disease, focusing on brain structures known to experience neuropathological changes. Major findings of our study were: (1) endothelial cell damage in capillary ultrastructure, compromising the BBB and resulting in vascular leakage, (2) formation of numerous large vacuoles in endothelial cells and perivascular cells (pericytes and perivascular macrophages) in the large majority of vessels, (3) edematous space around microvessels, (4) microaneurysm adjacent to a ruptured endothelium, (6) Evans Blue and albumin microvascular leakage in various brain structures, (7) GM3 ganglioside accumulation in endothelium of the brain microvasculature.

Conclusions/significance: These new findings of BBB structural and function impairment in MPS III B mice even at early disease stage may have implications for disease pathogenesis and should be considered in current and future development of treatments for MPS III B.

Show MeSH
Related in: MedlinePlus