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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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Related in: MedlinePlus

Electron microscope examination of the striatum of Naglu mutant mice.(A) Structural integrity of capillaries in the striatum was normal in C57 BL/6J control mice. (B) A single layer of endothelial cells surrounded by a layer of basement membrane in control mouse seen at high magnification. (C), (D) Edematous space and large vacuoles are indicated around vessels. Vacuolated pericytes can be seen in the striatum of early symptomatic Naglu mice. (E) Large vacuoles were found in endothelial cells and pericytes of late symptomatic animals. (F) A high magnification image of a capillary from the striatum of a 6 month old mutant mouse showing an endothelial cell with endoplasmic reticulum swelling and formation of a large vacuole in its cytoplasm. Edematous space has appeared around the capillary. Multiple layers of endothelial cells and basement membrane can be observed here, indicating a reparative process taking place. The luminal endothelial cells are damaged. EC - endothelial cell, BM - basement membrane, E – erythrocyte, m – mitochondrion, A – axon, P – pericyte, PM – perivascular macrophage, Nu – nucleus, V – vacuole, + - swollen endoplasmic reticulum, asterisks - microvilli, > - extracellular edematous space. Magnifications: (A), (C): 7,100x; (B), (E): 14,000x; (D): 8,900x; (F): 28,000x.
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pone-0016601-g003: Electron microscope examination of the striatum of Naglu mutant mice.(A) Structural integrity of capillaries in the striatum was normal in C57 BL/6J control mice. (B) A single layer of endothelial cells surrounded by a layer of basement membrane in control mouse seen at high magnification. (C), (D) Edematous space and large vacuoles are indicated around vessels. Vacuolated pericytes can be seen in the striatum of early symptomatic Naglu mice. (E) Large vacuoles were found in endothelial cells and pericytes of late symptomatic animals. (F) A high magnification image of a capillary from the striatum of a 6 month old mutant mouse showing an endothelial cell with endoplasmic reticulum swelling and formation of a large vacuole in its cytoplasm. Edematous space has appeared around the capillary. Multiple layers of endothelial cells and basement membrane can be observed here, indicating a reparative process taking place. The luminal endothelial cells are damaged. EC - endothelial cell, BM - basement membrane, E – erythrocyte, m – mitochondrion, A – axon, P – pericyte, PM – perivascular macrophage, Nu – nucleus, V – vacuole, + - swollen endoplasmic reticulum, asterisks - microvilli, > - extracellular edematous space. Magnifications: (A), (C): 7,100x; (B), (E): 14,000x; (D): 8,900x; (F): 28,000x.

Mentions: Brain structures of control mice (10–12 months old) were characterized by normal appearance of neurons, myelinated axons, capillaries, and surrounding astrocytes (Figures 1–4, A, B). All blood vessels were surrounded by healthy neuroglia cell processes. Erythrocytes were observed in the lumen of the capillaries. Cell organelles were well preserved and mitochondria showed a normal pattern of cristae. Capillaries consisted of a single layer of endothelial cells surrounded by a layer of basement membrane, forming an intact BBB.


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)

Electron microscope examination of the striatum of Naglu mutant mice.(A) Structural integrity of capillaries in the striatum was normal in C57 BL/6J control mice. (B) A single layer of endothelial cells surrounded by a layer of basement membrane in control mouse seen at high magnification. (C), (D) Edematous space and large vacuoles are indicated around vessels. Vacuolated pericytes can be seen in the striatum of early symptomatic Naglu mice. (E) Large vacuoles were found in endothelial cells and pericytes of late symptomatic animals. (F) A high magnification image of a capillary from the striatum of a 6 month old mutant mouse showing an endothelial cell with endoplasmic reticulum swelling and formation of a large vacuole in its cytoplasm. Edematous space has appeared around the capillary. Multiple layers of endothelial cells and basement membrane can be observed here, indicating a reparative process taking place. The luminal endothelial cells are damaged. EC - endothelial cell, BM - basement membrane, E – erythrocyte, m – mitochondrion, A – axon, P – pericyte, PM – perivascular macrophage, Nu – nucleus, V – vacuole, + - swollen endoplasmic reticulum, asterisks - microvilli, > - extracellular edematous space. Magnifications: (A), (C): 7,100x; (B), (E): 14,000x; (D): 8,900x; (F): 28,000x.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3049764&req=5

pone-0016601-g003: Electron microscope examination of the striatum of Naglu mutant mice.(A) Structural integrity of capillaries in the striatum was normal in C57 BL/6J control mice. (B) A single layer of endothelial cells surrounded by a layer of basement membrane in control mouse seen at high magnification. (C), (D) Edematous space and large vacuoles are indicated around vessels. Vacuolated pericytes can be seen in the striatum of early symptomatic Naglu mice. (E) Large vacuoles were found in endothelial cells and pericytes of late symptomatic animals. (F) A high magnification image of a capillary from the striatum of a 6 month old mutant mouse showing an endothelial cell with endoplasmic reticulum swelling and formation of a large vacuole in its cytoplasm. Edematous space has appeared around the capillary. Multiple layers of endothelial cells and basement membrane can be observed here, indicating a reparative process taking place. The luminal endothelial cells are damaged. EC - endothelial cell, BM - basement membrane, E – erythrocyte, m – mitochondrion, A – axon, P – pericyte, PM – perivascular macrophage, Nu – nucleus, V – vacuole, + - swollen endoplasmic reticulum, asterisks - microvilli, > - extracellular edematous space. Magnifications: (A), (C): 7,100x; (B), (E): 14,000x; (D): 8,900x; (F): 28,000x.
Mentions: Brain structures of control mice (10–12 months old) were characterized by normal appearance of neurons, myelinated axons, capillaries, and surrounding astrocytes (Figures 1–4, A, B). All blood vessels were surrounded by healthy neuroglia cell processes. Erythrocytes were observed in the lumen of the capillaries. Cell organelles were well preserved and mitochondria showed a normal pattern of cristae. Capillaries consisted of a single layer of endothelial cells surrounded by a layer of basement membrane, forming an intact BBB.

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