Impaired blood–brain and blood–spinal cord barriers in mutant SOD1-linked ALS rat

Nicaise, Charles; Mitrečić, Dinko; Demetter, Pieter; Decker, Robert De; Authelet, Michèle; Boom, Alain; Pochet, Roland

doi:10.1016/j.brainres.2009.09.018

Cited by 144 publications

(145 citation statements)

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“…In a rat SOD1 model of amyotrophic lateral sclerosis, IgG and hemosiderin were detected in presymptomatic stages, and Evans blue dye extravasation was evident in symptomatic stages. 53 Recent findings in pericyte-deficient mice demonstrated that BBB breakdown causes secondary dendritic damage and neuronal loss. 54 This suggests that accumulation of serum proteins in the AAV-tauP301L model may further contribute to dendritic degeneration.…”

Section: Tau-mediated Neurodegeneration Is Closely Linked To Neurovasmentioning

confidence: 99%

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

Jaworski

Lechat

Demedts

et al. 2011

The American Journal of Pathology

105

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Adeno-associated virus (AAV)-mediated expression of wild-type or mutant P301L protein tau produces massive degeneration of pyramidal neurons without protein tau aggregation. We probed this novel model for genetic and structural factors and early parameters of pyramidal neurodegeneration. In yellow fluorescent protein-expressing transgenic mice, intracerebral injection of AAV-tauP301L revealed early damage to apical dendrites of CA1 pyramidal neurons, whereas their somata remained normal. Ultrastructurally, more and enlarged autophagic vacuoles were contained in degenerating dendrites and manifested as dark, discontinuous, vacuolated processes surrounded by activated astrocytes. Dendritic spines were lost in AAV-tauP301L-injected yellow fluorescent protein-expressing transgenic mice, and ultrastructurally, spines appeared dark and degenerating. In CX3CR1 EGFP/EGFP -deficient mice, microglia were recruited early to neurons expressing human tau. The inflammatory response was accompanied by extravasation of plasma immunoglobulins. ␣2-Macroglobulin, but neither albumin nor transferrin, became lodged in the brain parenchyma. Large proteins, but not Evans blue, entered the brain of mice injected with AAV-tauP301L. Ultrastructurally, brain capillaries were constricted and surrounded by swollen astrocytes with extensions that contacted degenerating dendrites and axons. Together, these data corroborate the hypothesis that neuroinflammation participates essentially in tau-mediated neurodegeneration, and the model recapitulates early dendritic defects reminiscent of "dendritic amputation" in Alzheimer's disease.

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Section: Tau-mediated Neurodegeneration Is Closely Linked To Neurovasmentioning

confidence: 99%

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

Jaworski

Lechat

Demedts

et al. 2011

The American Journal of Pathology

105

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“…The immunohistochemistry analyses were realized using a previously described method [15]. After fixation of the organs in 10% formalin followed by a paraffin-embedding procedure, 7µm-sections were rehydrated, endogenous peroxidases were blocked (0.3% H2O2 in methanol) and non-specific binding antibodies inhibited for 1 hour with 10% goat serum.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Glucose Transport by Acinar Cells in Rat Parotid Glands

Jurysta¹,

Nicaise

Cetik³

et al. 2012

Cell Physiol Biochem

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Background/Aims: Salivary glucose is often considered as being from glandular origin. Little information is available, however, on the possible role of glucose transporters in the secretion of the hexose by salivary glands. The major aim of the present study was to investigate the expression and localization of several distinct glucose transporters in acinar cells of rat parotid glands. Methods: Quantitative real-time PCR analysis, immunohistochemistry and western blotting techniques were used to assess the presence of SGLT1, GLUT1, GLUT2 and GLUT4 in acinar cells of rat parotid glands. Results: Quantitative real-time PCR documented the expression of SGLT1 and GLUT1 in parotid tissues, with a much lower level of GLUT4 mRNA and no expression of GLUT2 mRNA. Western blot analysis revealed the presence of SGLT1, GLUT1 and GLUT4 proteins, but not GLUT2 proteins in the parotid extract. Immunohistochemistry confirmed these findings. SGLT1 was specifically located at the baso-lateral membrane, co-localizing with Na⁺/K⁺ ATPase. GLUT1 was found both at the baso-lateral and apical level. GLUT4 appeared to be also located at the baso-lateral level. However, too little GLUT4 was present to allow co-localization labeling. Conclusion: Based on these findings, a model is proposed for the transport of glucose into the acinar cells and thereafter into the acinar lumen.

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“…Pathophysiology of ALS is poorly understood and likely multifactorial. Proposed starting points for this complex disease targeting the motor neuron population include mitochondrial dysfunction, intracellular protein aggregation, disturbances of RNA metabolism, extracellular toxic environment, impairment at the level of axonal transport and at the neuromuscular synapse (reviewed by [81] ), together with extrinsic events: blood-brain barrier breakdown, glial cell reaction/dysfunction and neuroinflammation [82][83][84][85][86][87][88] . It is known that dying motor neurons influence surrounding cells, of which astrocytes are most commonly investigated.…”

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confidence: 99%

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

Nicaise

Mitrečić

Falnikar

et al. 2015

WJSC

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in experimental ALS and SCI models and we discuss avenues for future directions based on latest molecular findings regarding astrocyte biology. Core tip: Amyotrophic lateral sclerosis (ALS) and spinal cord injury (SCI) result in incurable neurological dysfunction due to loss of spinal motor neurons and axonal degeneration, amongst other mechanisms. Astrocytes are increasingly recognized as being necessary for neuroprotection and regeneration in the central nervous system as they promote axonal growth and deliver essential neurotrophic factors under both physiological and pathophysiological conditions. Given the central role played by astrocytes, we gathered convincing results from ALS and SCI literature that argue in favor of stem cell-based astrocyte replacement therapies and stress the scientific community to investigate more deeply the molecular understanding of astrocyte biology. MULTIPLE FACETS OF ASTROCYTES IN THE CENTRAL NERVOUS SYSTEM Astrocyte functionsAstrocytes are the most abundant cells in the central nervous system (CNS), outnumbering neuronal cells by several fold in some CNS regions. They have long been relegated to a secondary position, behind neurons or oligodendrocytes, as many thought that astrocytes were barely by-standers of the CNS. Accounting for a large fraction of the brain volume, their particular shape and tissue distribution are known to elaborate an extensive network of fine interconnected processes. Their star-shaped morphology projecting long branched processes provides a large coverage of CNS structures and the ensheathment of the brain or spinal cord in the pia matter. They draw the whole brain microanatomy by secreting astrocyte-derived extracellular matrix proteins (e.g., chondroitin sulfate proteoglycans, hyaluronan, tenascin proteins family, thrombospondin), thereby providing structural support for nervous system cells. Beside their structural role, astrocytes are recognized to fulfill and support many, if not all, functions of the healthy CNS [1] . Astrocyte endfeet cover more than 90% of the CNS vasculature and come in contact with endothelial cells. Expressing key glucose transporter-1, astrocytes convoy glucose from blood vessels to nervous system cells, most of them being devoid of direct access to this high-end source of energy. Hence, astrocytes synthetize via specific metabolic pathways glycogen and lactate, main energy fuels for neurons or distant synapses. Through humoral factors released at the perivascular space, astrocytes control local cerebral blood flow and bloodbrain barrier (BBB) integrity. Transforming growth factor-beta, glial-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2) and angiopoietin 1 (binding the endothelium-specific receptor TIE2), all secreted at the vascular end-feet, act on endothelial cells in order to induce or maintain an operational BBB [2,3] . Astrocytes-released growth factors [e.g., brainderived neurotrophic factor, BDNF; ciliary neurotrophic factor (CNTF)] exert beneficial effects far beyond the perivascular spa...

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Impaired blood–brain and blood–spinal cord barriers in mutant SOD1-linked ALS rat

Cited by 144 publications

References 37 publications

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

Dendritic Degeneration, Neurovascular Defects, and Inflammation Precede Neuronal Loss in a Mouse Model for Tau-Mediated Neurodegeneration

Glucose Transport by Acinar Cells in Rat Parotid Glands

Transplantation of stem cell-derived astrocytes for the treatment of amyotrophic lateral sclerosis and spinal cord injury

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