Altered blood–brain barrier development in dystrophic MDX mice

Nico, Beatrice; Nicchia, Grazia Paola; Frigeri, Antonio; Corsi, Patrizia; Mangieri, Domenica; Ribatti, Doménico; Svelto, María; Roncali, Luisa

doi:10.1016/j.neuroscience.2004.02.008

Cited by 84 publications

(64 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the brain, they are mainly expressed in perivascular astrocytes and in choroid plexuses, suggesting a potential role in water homeostasis, regulation of transport mechanisms across BBB and cerebrospinal fluid production. 7,10,19,31,39,44 Mutations of DAPs are involved in muscular dystrophy, 45 and are responsible for structural and biochemical changes in the brain. 46 The dystrophin isoform Dp71 is localized in the perivascular glial endfeet, in which it is involved in BBB maturation 39,47 and in the clustering of the AQP4 water channel on the astrocyte glial membranes.…”

Section: Discussionmentioning

confidence: 99%

“…7,10,19,31,39,44 Mutations of DAPs are involved in muscular dystrophy, 45 and are responsible for structural and biochemical changes in the brain. 46 The dystrophin isoform Dp71 is localized in the perivascular glial endfeet, in which it is involved in BBB maturation 39,47 and in the clustering of the AQP4 water channel on the astrocyte glial membranes. 48 Glial DAPs, laminin and agrin in mdx mice B Nico et al AQP4 controls BBB functioning and integrity, because its expression parallels BBB development and is altered after BBB damage.…”

Section: Discussionmentioning

confidence: 99%

“…39 AQP4 is also connected with the a-b complex and a-DG is linked to laminin and agrin, a proteoglycan present in the basement membrane of cerebral capillaries, involved in BBB integrity. 56 Moreover, the correct AQP4 and Kir 4.1 clustering on glial membranes required a-DG and laminin.…”

Section: Discussionmentioning

confidence: 99%

“…34,37 In the past, we have extensively investigated BBB alterations in mdx mice, involving an increment in vascular permeability associated with structural and molecular alterations in endothelial and glial cells with AQP4 reduction and edema. 38 Moreover, we have demonstrated that mdx BBB alterations are coupled with a significant reduction in the short dystrophin isoform (Dp71) at glial endfeet during development, 39 an increased immunoreactivity to vascular endothelial growth factor (VEGF) in neurons and to VEGF receptor-2 (VEGFR-2) in cerebral endothelial cells, 40 a high expression of matrix metalloproteinases (MMPs) in the mdx brain. 41 Finally, we have shown that, in the brain of mdx mouse, hypoxia-inducible factor-1a is activated in neurons and astrocytes.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

Nico

Tamma

Annese

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

In this study, we investigated the involvement of dystrophin-associated proteins (DAPs) and their relationship with the perivascular basement membrane in the brains of mdx mice and controls at the age of 2 months. We analyzed (1) the expression of glial DAPs a-b-dystroglycan (DG), a-syntrophin, aquaporin-4 (AQP4) water channel, Kir 4.1 and dystrophin isoform (Dp71) by immunocytochemistry, laser confocal microscopy, immunogold electron microscopy, immunoblotting and RT-PCR; (2) the ultrastructure of the basement membrane and expression of laminin and agrin; and (3) the dual immunofluorescence colocalization of AQP4/a-b-DG, and of Kir 4.1/agrin. The following results were observed in mdx brain as compared with controls: (1) a significant reduction in protein content and mRNA expression of DAPs; (2) ultrastructurally, a thickened and discontinuous appearance of the basement membrane and a significant reduction in laminin and agrin; and (3) a molecular rearrangment of a-b-DG, coupled with a parallel loss of agrin and Kir 4.1 on basement membrane and glial endfeet. These data indicate that in mdx brain the deficiency in dystrophin and dystrophin isoform (Dp71) is coupled with a reduction of DAP components, coupled with an altered anchoring to the basement membrane. The blood-brain barrier (BBB) controls the selective exchanges between blood and neuropil by specific molecular and structural features of its vascular and perivascular components, including endothelial cells, pericytes, glial endfeet and basement membrane. 1-3 Glial cells have a key role in the control of BBB development and integrity. They express in a polarized way, on their perivascular endfeet, carrier membranes and channel proteins, including aquaporin-4 (AQP4) water channel and potassium channel Kir 4.1, which are responsible for the water flow rate and spatial K þ buffering control. [4][5][6][7][8][9] In the retina, AQP4 colocalizes with Kir 4.1, 9-11 suggesting a tight cooperation between the water flux and K þ siphoning generated by neuronal activity at the BBB interfaces. Moreover, AQP4 and Kir 4.1 rearrangement has been described in BBB alterations, coupled with cytotoxic edema and K þ -delayed buffering capacity. 12,13 AQP4 has a crucial role in the regulation of the interactions occurring between endothelial and glial cells and between glial cells and the extracellular matrix components. AQP4 is a component of the orthogonal aggregate particles (OAPs), demonstrated by freeze fracturing on the ependimoglial membrane and perivascular glial endfeet, 14 the development of which occurs in parallel with AQP4 glial endfeet expression and BBB maturation. 7 Moreover, OAPs contain AQP4 associated with Kir 4.1 12 and their polarized distribution on the glial endfeet seems to be dependent by the presence of the perivascular basement membrane. 15 AQP4 controls BBB functioning, modifying

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

Nico

Tamma

Annese

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…Dystrophin and utrophin isoforms also function in non-neuronal cells of the vertebrate nervous system (Table 1), and disruption of these non-neuronal functions may contribute to the neurological symptoms associated with Muscular Dystrophy (Moizard et al, 1998;Nico et al, 2004). Specifically, the short dystrophin isoform, Dp71, is expressed at glial endfeet that surround blood vessels in the CNS and is essential for maintenance of blood-brain barrier integrity Connors and Kofuji, 2002;Dalloz et al, 2003;AmiryMoghaddam et al, 2004;Connors et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

2008

View full text Add to dashboard Cite

Muscular dystrophy patients often show cognitive impairment, in addition to muscle degeneration caused by dystrophin gene defects. The cognitive impairments lead to speculation that the dystrophin protein family may play a key role at neuronal synapses. Dystrophin regulates the stability of selected GABA A receptor subtypes and α3-containing nicotinic acetylcholine receptors (nAChRs) at a subset of central GABAergic and peripheral sympathetic nicotinic neuron synapses. Similarly, utrophin, the autosomal homologue of dystrophin, is not required for clustering but indirectly stabilizes muscletype nAChRs at the neuromuscular junction. We examined dystrophin and utrophin expression and localization in the avian parasympathetic ciliary ganglion (CG) to determine whether these proteins play a general role at neuronal nicotinic synapses. We have determined that full-length utrophin and dystrophin and the short dystrophin isoform Dp116 are the major isoforms expressed in the CG based on immunoblotting and immunolabeling. Unexpectedly, the cytoskeletal proteins were not detected at nicotinic synapses or in CG neurons. They are expressed in myelinating and non-myelinating Schwann cells. Further, utrophin expression developmentally precedes that of dystrophin. The proteins show partially overlapping distributions, but also differential accumulation along the surface membrane of Schwann cells adjacent to neuronal somata versus axonal processes. Our findings are consistent with reports that dystrophin protein family members function in the maintenance of cellcell interactions and myelination by anchoring the Schwann cell surface membrane to the basal lamina. In contrast, our results differ from those in skeletal muscle and a subset of sympathetic neurons where utrophin and dystrophin localize at nicotinic synapses.

show abstract

Responsive Astrocytic Endfeet: The Role of AQP4 in BBB Development and Functioning

Nicchia

Nico

Camassa

et al. 2006

Blood‐Brain Barriers

View full text Add to dashboard Cite

Altered blood–brain barrier development in dystrophic MDX mice

Cited by 84 publications

References 72 publications

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse

Dystrophin and utrophin isoforms are expressed in glia, but not neurons, of the avian parasympathetic ciliary ganglion

Responsive Astrocytic Endfeet: The Role of AQP4 in BBB Development and Functioning

Contact Info

Product

Resources

About