scholarly journals Mitochondria-ER contacts in reactive astrocytes coordinate local perivascular domains to promote vascular remodelling

2019 ◽  
Author(s):  
Jana Goebel ◽  
Esther Engelhardt ◽  
Patric Pelzer ◽  
Vignesh Sakthivelu ◽  
Hannah M. Jahn ◽  
...  
Keyword(s):  
Structural Changes ◽  
Mitochondrial Dynamics ◽  
Tissue Level ◽  
Acute Injury ◽  
Mitofusin 2 ◽  
Blood Brain Barrier Disruption ◽  
Conditional Deletion ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms

SummaryAstrocytes have emerged for playing important roles in brain tissue repair, however the underlying mechanisms remain poorly understood. We show that acute injury and blood-brain barrier disruption trigger the formation of a prominent mitochondrial-enriched compartment in astrocytic end-feet which enables vascular remodeling. Integrated imaging approaches revealed that this mitochondrial clustering is part of an adaptive response regulated by fusion dynamics. Astrocyte-specific conditional deletion of Mitofusin 2 (Mfn2) suppressed perivascular mitochondrial clustering and disrupted mitochondria-ER contact sites. Functionally, two-photon imaging experiments showed that these structural changes were mirrored by impaired mitochondrial Ca2+ uptake leading to abnormal cytosolic transients within end-feet in vivo. At the tissue level, a compromised vascular complexity in the lesioned area was restored by boosting mitochondrial-ER perivascular tethering in MFN2-deficient astrocytes. These data unmask a crucial role for mitochondrial dynamics in coordinating astrocytic local domains and have important implications for repairing the injured brain.

scholarly journals Blood–brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bailey Hiles-Murison ◽  
Andrew P. Lavender ◽  
Mark J. Hackett ◽  
Joshua J. Armstrong ◽  
Michael Nesbit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Hippocampal Formation ◽  
Brain Barrier ◽  
Lateral Ventricles ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms

AbstractRepeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood–brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

scholarly journals Blood-brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks

2021 ◽  
Author(s):  
Bailey Hiles-Murison ◽  
Andrew Lavender ◽  
Mark Hackett ◽  
Joshua Armstrong ◽  
Michael Nesbit ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Brain Barrier ◽  
Hippocampal Formation ◽  
Brain Barrier ◽  
Lateral Ventricles ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms

Abstract Repeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood-brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

scholarly journals Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease

2016 ◽  
Vol 113 (12) ◽  
pp. 3323-3328 ◽  
Author(s):  
Anne-Christine Flach ◽  
Tanja Litke ◽  
Judith Strauss ◽  
Michael Haberl ◽  
César Cordero Gómez ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Nervous Tissue ◽  
Immune Cell ◽  
Clinical Disease ◽  
Blood Brain Barrier Disruption ◽  
Cns Autoimmunity ◽  
Brain Barrier Disruption ◽  
Underlying Mechanisms ◽  
Antigen Presenting

Multiple sclerosis (MS) is caused by T cells that are reactive for brain antigens. In experimental autoimmune encephalomyelitis, the animal model for MS, myelin-reactive T cells initiate the autoimmune process when entering the nervous tissue and become reactivated upon local encounter of their cognate CNS antigen. Thereby, the strength of the T-cellular reactivation process within the CNS tissue is crucial for the manifestation and the severity of the clinical disease. Recently, B cells were found to participate in the pathogenesis of CNS autoimmunity, with several diverse underlying mechanisms being under discussion. We here report that B cells play an important role in promoting the initiation process of CNS autoimmunity. Myelin-specific antibodies produced by autoreactive B cells after activation in the periphery diffused into the CNS together with the first invading pathogenic T cells. The antibodies accumulated in resident antigen-presenting phagocytes and significantly enhanced the activation of the incoming effector T cells. The ensuing strong blood–brain barrier disruption and immune cell recruitment resulted in rapid manifestation of clinical disease. Therefore, myelin oligodendrocyte glycoprotein (MOG)-specific autoantibodies can initiate disease bouts by cooperating with the autoreactive T cells in helping them to recognize their autoantigen and become efficiently reactivated within the immune-deprived nervous tissue.

scholarly journals Rapid, Nitric Oxide Synthesis-Dependent Activation of MMP-9 at Pericyte Somata During Capillary Ischemia in vivo

2021 ◽  
Vol 11 ◽  
Author(s):  
Robert G. Underly ◽  
Andy Y. Shih
Keyword(s):  
Nitric Oxide ◽  
Protein Synthesis ◽  
Vascular Pathology ◽  
Blood Brain Barrier Disruption ◽  
Vascular Physiology ◽  
Brain Barrier Disruption ◽  
Inhibitor Of Protein Synthesis ◽  
Oxide Synthase ◽  
Nos Isoforms

Nitric oxide serves essential roles in normal vascular physiology, but paradoxically contributes to vascular pathology in disease. During brain ischemia, aberrant nitric oxide levels can cause cellular injury through induction of nitrosative/oxidative stress and post-translational activation of matrix-metalloproteinase-9 (MMP-9). We recently demonstrated that brain pericyte somata were associated with very early and localized MMP-9 activation along capillaries during cerebral ischemia, leading to focal blood-brain barrier disruption. Here, we tested whether this effect was dependent upon nitric oxide production. In vivo two-photon imaging was used to directly visualize MMP9 activity using a FITC-gelatin probe and leakage of intravenous dye during photothrombotically induced capillary ischemia. Results showed that the NOS inhibitor, L-NIL, at concentrations affecting both iNOS and constitutive NOS isoforms, attenuated capillary leakage at pericyte soma-specific locations and substantially reduced FITC-gelatin cleavage. We also found that combined administration of L-NIL and anisomycin, an inhibitor of protein synthesis, led to near complete elimination of FITC-gelatin cleavage and vascular leakage. These results indicate that both nitric oxide synthase and new protein synthesis are involved in the rapid activation of MMP-9 at somata of capillary pericytes during ischemia.

Radiographic quantitation of reversible blood-brain barrier disruption in vivo.

Radiology ◽  
1982 ◽  
Vol 143 (1) ◽  
pp. 85-89 ◽  
Author(s):  
B P Drayer ◽  
D E Schmeckel ◽  
L W Hedlund ◽  
M M Lischko ◽  
M R Sage ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Barrier Disruption ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Brain Barrier Disruption
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