TY  - JOUR
AU  - Kisler, Kassandra
AU  - Nikolakopoulou, Angeliki M.
AU  - Sweeney, Melanie D.
AU  - Lazić, Divna
AU  - Zhao, Zhen
AU  - Zloković, Berislav V.
PY  - 2020
UR  - https://www.frontiersin.org/article/10.3389/fncel.2020.00027/full
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3663
AB  - Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer's disease (AD) and other neurogenerative disorders.
PB  - Frontiers Media SA
T2  - Frontiers in Cellular Neuroscience
T1  - Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling
VL  - 14
DO  - 10.3389/fncel.2020.00027
SP  - 27
ER  - 

@article{
author = "Kisler, Kassandra and Nikolakopoulou, Angeliki M. and Sweeney, Melanie D. and Lazić, Divna and Zhao, Zhen and Zloković, Berislav V.",
year = "2020",
abstract = "Pericytes are perivascular mural cells that enwrap brain capillaries and maintain blood-brain barrier (BBB) integrity. Most studies suggest that pericytes regulate cerebral blood flow (CBF) and oxygen delivery to activated brain structures, known as neurovascular coupling. While we have previously shown that congenital loss of pericytes leads over time to aberrant hemodynamic responses, the effects of acute global pericyte loss on neurovascular coupling have not been studied. To address this, we used our recently reported inducible pericyte-specific Cre mouse line crossed to iDTR mice carrying Cre-dependent human diphtheria toxin (DT) receptor, which upon DT treatment leads to acute pericyte ablation. As expected, DT led to rapid progressive loss of pericyte coverage of cortical capillaries up to 50% at 3 days post-DT, which correlated with approximately 50% reductions in stimulus-induced CBF responses measured with laser doppler flowmetry (LDF) and/or intrinsic optical signal (IOS) imaging. Endothelial response to acetylcholine, microvascular density, and neuronal evoked membrane potential responses remained, however, unchanged, as well as arteriolar smooth muscle cell (SMC) coverage and functional responses to adenosine, as we previously reported. Together, these data suggest that neurovascular uncoupling in this model is driven by pericyte loss, but not other vascular deficits or neuronal dysfunction. These results further support the role of pericytes in CBF regulation and may have implications for neurological conditions associated with rapid pericyte loss such as hypoperfusion and stroke, as well as conditions where the exact time course of global regional pericyte loss is less clear, such as Alzheimer's disease (AD) and other neurogenerative disorders.",
publisher = "Frontiers Media SA",
journal = "Frontiers in Cellular Neuroscience",
title = "Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling",
volume = "14",
doi = "10.3389/fncel.2020.00027",
pages = "27"
}

Kisler, K., Nikolakopoulou, A. M., Sweeney, M. D., Lazić, D., Zhao, Z.,& Zloković, B. V.. (2020). Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling. in Frontiers in Cellular Neuroscience
Frontiers Media SA., 14, 27.
https://doi.org/10.3389/fncel.2020.00027

Kisler K, Nikolakopoulou AM, Sweeney MD, Lazić D, Zhao Z, Zloković BV. Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling. in Frontiers in Cellular Neuroscience. 2020;14:27.
doi:10.3389/fncel.2020.00027 .

Kisler, Kassandra, Nikolakopoulou, Angeliki M., Sweeney, Melanie D., Lazić, Divna, Zhao, Zhen, Zloković, Berislav V., "Acute Ablation of Cortical Pericytes Leads to Rapid Neurovascular Uncoupling" in Frontiers in Cellular Neuroscience, 14 (2020):27,
https://doi.org/10.3389/fncel.2020.00027 . .

TY  - JOUR
AU  - Nikolakopoulou, Angeliki M.
AU  - Montagne, Axel
AU  - Kisler, Kassandra
AU  - Dai, Zhonghua
AU  - Wang, Yaoming
AU  - Huuskonen, Mikko T.
AU  - Sagare, Abhay P.
AU  - Lazić, Divna
AU  - Sweeney, Melanie D.
AU  - Kong, Pan
AU  - Wang, Min
AU  - Owens, Nelly Chuqui
AU  - Lawson, Erica J.
AU  - Xie, Xiaochun
AU  - Zhao, Zhen
AU  - Zloković, Berislav V.
PY  - 2019
UR  - http://www.nature.com/articles/s41593-019-0434-z
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3388
AB  - Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.
T2  - Nature Neuroscience
T1  - Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.
IS  - 7
VL  - 22
DO  - 10.1038/s41593-019-0434-z
SP  - 1089
EP  - 1098
ER  - 

@article{
author = "Nikolakopoulou, Angeliki M. and Montagne, Axel and Kisler, Kassandra and Dai, Zhonghua and Wang, Yaoming and Huuskonen, Mikko T. and Sagare, Abhay P. and Lazić, Divna and Sweeney, Melanie D. and Kong, Pan and Wang, Min and Owens, Nelly Chuqui and Lawson, Erica J. and Xie, Xiaochun and Zhao, Zhen and Zloković, Berislav V.",
year = "2019",
abstract = "Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here we generate an inducible pericyte-specific Cre line and cross pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor. After pericyte ablation with diphtheria toxin, mice showed acute blood-brain barrier breakdown, severe loss of blood flow, and a rapid neuron loss that was associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing of pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade that links pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings may have implications for the pathogenesis and treatment of neurological disorders that are associated with pericyte loss and/or neurovascular dysfunction.",
journal = "Nature Neuroscience",
title = "Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.",
number = "7",
volume = "22",
doi = "10.1038/s41593-019-0434-z",
pages = "1089-1098"
}

Nikolakopoulou, A. M., Montagne, A., Kisler, K., Dai, Z., Wang, Y., Huuskonen, M. T., Sagare, A. P., Lazić, D., Sweeney, M. D., Kong, P., Wang, M., Owens, N. C., Lawson, E. J., Xie, X., Zhao, Z.,& Zloković, B. V.. (2019). Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.. in Nature Neuroscience, 22(7), 1089-1098.
https://doi.org/10.1038/s41593-019-0434-z

Nikolakopoulou AM, Montagne A, Kisler K, Dai Z, Wang Y, Huuskonen MT, Sagare AP, Lazić D, Sweeney MD, Kong P, Wang M, Owens NC, Lawson EJ, Xie X, Zhao Z, Zloković BV. Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss.. in Nature Neuroscience. 2019;22(7):1089-1098.
doi:10.1038/s41593-019-0434-z .

Nikolakopoulou, Angeliki M., Montagne, Axel, Kisler, Kassandra, Dai, Zhonghua, Wang, Yaoming, Huuskonen, Mikko T., Sagare, Abhay P., Lazić, Divna, Sweeney, Melanie D., Kong, Pan, Wang, Min, Owens, Nelly Chuqui, Lawson, Erica J., Xie, Xiaochun, Zhao, Zhen, Zloković, Berislav V., "Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss." in Nature Neuroscience, 22, no. 7 (2019):1089-1098,
https://doi.org/10.1038/s41593-019-0434-z . .

TY  - JOUR
AU  - Lazić, Divna
AU  - Sagare, Abhay P
AU  - Nikolakopoulou, Angeliki M
AU  - Griffin, John H
AU  - Vassar, Robert
AU  - Zloković, Berislav V
PY  - 2019
UR  - http://www.ncbi.nlm.nih.gov/pubmed/30647119
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3263
AB  - 3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer's disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40-50%, which is mediated through NFκB-dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.
T2  - The Journal of Experimental Medicine
T1  - 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.
IS  - 2
VL  - 216
DO  - 10.1084/jem.20181035
SP  - 279
EP  - 293
ER  - 

@article{
author = "Lazić, Divna and Sagare, Abhay P and Nikolakopoulou, Angeliki M and Griffin, John H and Vassar, Robert and Zloković, Berislav V",
year = "2019",
abstract = "3K3A-activated protein C (APC), a cell-signaling analogue of endogenous blood serine protease APC, exerts vasculoprotective, neuroprotective, and anti-inflammatory activities in rodent models of stroke, brain injury, and neurodegenerative disorders. 3K3A-APC is currently in development as a neuroprotectant in patients with ischemic stroke. Here, we report that 3K3A-APC inhibits BACE1 amyloidogenic pathway in a mouse model of Alzheimer's disease (AD). We show that a 4-mo daily treatment of 3-mo-old 5XFAD mice with murine recombinant 3K3A-APC (100 µg/kg/d i.p.) prevents development of parenchymal and cerebrovascular amyloid-β (Aβ) deposits by 40-50%, which is mediated through NFκB-dependent transcriptional inhibition of BACE1, resulting in blockade of Aβ generation in neurons overexpressing human Aβ-precursor protein. Consistent with reduced Aβ deposition, 3K3A-APC normalized hippocampus-dependent behavioral deficits and cerebral blood flow responses, improved cerebrovascular integrity, and diminished neuroinflammatory responses. Our data suggest that 3K3A-APC holds potential as an effective anti-Aβ prevention therapy for early-stage AD.",
journal = "The Journal of Experimental Medicine",
title = "3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.",
number = "2",
volume = "216",
doi = "10.1084/jem.20181035",
pages = "279-293"
}

Lazić, D., Sagare, A. P., Nikolakopoulou, A. M., Griffin, J. H., Vassar, R.,& Zloković, B. V.. (2019). 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.. in The Journal of Experimental Medicine, 216(2), 279-293.
https://doi.org/10.1084/jem.20181035

Lazić D, Sagare AP, Nikolakopoulou AM, Griffin JH, Vassar R, Zloković BV. 3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice.. in The Journal of Experimental Medicine. 2019;216(2):279-293.
doi:10.1084/jem.20181035 .

Lazić, Divna, Sagare, Abhay P, Nikolakopoulou, Angeliki M, Griffin, John H, Vassar, Robert, Zloković, Berislav V, "3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice." in The Journal of Experimental Medicine, 216, no. 2 (2019):279-293,
https://doi.org/10.1084/jem.20181035 . .

TY  - JOUR
AU  - Montagne, Axel
AU  - Nikolakopoulou, Angeliki M
AU  - Zhao, Zhen
AU  - Sagare, Abhay P
AU  - Si, Gabriel
AU  - Lazic, Divna
AU  - Barnes, Samuel R
AU  - Daianu, Madelaine
AU  - Ramanathan, Anita
AU  - Go, Ariel
AU  - Lawson, Erica J
AU  - Wang, Yaoming
AU  - Mack, William J
AU  - Thompson, Paul M
AU  - Schneider, Julie A
AU  - Varkey, Jobin
AU  - Langen, Ralf
AU  - Mullins, Eric
AU  - Jacobs, Russell E
AU  - Zlokovic, Berislav V
PY  - 2018
UR  - http://www.nature.com/doifinder/10.1038/nm.4482
UR  - http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC5840035
UR  - https://radar.ibiss.bg.ac.rs/handle/123456789/3012
AB  - Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.
T2  - Nature Medicine
T2  - Nature Medicine
T1  - Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.
IS  - 3
VL  - 24
DO  - 10.1038/nm.4482
SP  - 326
EP  - 337
ER  - 

@article{
author = "Montagne, Axel and Nikolakopoulou, Angeliki M and Zhao, Zhen and Sagare, Abhay P and Si, Gabriel and Lazic, Divna and Barnes, Samuel R and Daianu, Madelaine and Ramanathan, Anita and Go, Ariel and Lawson, Erica J and Wang, Yaoming and Mack, William J and Thompson, Paul M and Schneider, Julie A and Varkey, Jobin and Langen, Ralf and Mullins, Eric and Jacobs, Russell E and Zlokovic, Berislav V",
year = "2018",
abstract = "Diffuse white-matter disease associated with small-vessel disease and dementia is prevalent in the elderly. The biological mechanisms, however, remain elusive. Using pericyte-deficient mice, magnetic resonance imaging, viral-based tract-tracing, and behavior and tissue analysis, we found that pericyte degeneration disrupted white-matter microcirculation, resulting in an accumulation of toxic blood-derived fibrin(ogen) deposits and blood-flow reductions, which triggered a loss of myelin, axons and oligodendrocytes. This disrupted brain circuits, leading to white-matter functional deficits before neuronal loss occurs. Fibrinogen and fibrin fibrils initiated autophagy-dependent cell death in oligodendrocyte and pericyte cultures, whereas pharmacological and genetic manipulations of systemic fibrinogen levels in pericyte-deficient, but not control mice, influenced the degree of white-matter fibrin(ogen) deposition, pericyte degeneration, vascular pathology and white-matter changes. Thus, our data indicate that pericytes control white-matter structure and function, which has implications for the pathogenesis and treatment of human white-matter disease associated with small-vessel disease.",
journal = "Nature Medicine, Nature Medicine",
title = "Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.",
number = "3",
volume = "24",
doi = "10.1038/nm.4482",
pages = "326-337"
}

Montagne, A., Nikolakopoulou, A. M., Zhao, Z., Sagare, A. P., Si, G., Lazic, D., Barnes, S. R., Daianu, M., Ramanathan, A., Go, A., Lawson, E. J., Wang, Y., Mack, W. J., Thompson, P. M., Schneider, J. A., Varkey, J., Langen, R., Mullins, E., Jacobs, R. E.,& Zlokovic, B. V.. (2018). Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.. in Nature Medicine, 24(3), 326-337.
https://doi.org/10.1038/nm.4482

Montagne A, Nikolakopoulou AM, Zhao Z, Sagare AP, Si G, Lazic D, Barnes SR, Daianu M, Ramanathan A, Go A, Lawson EJ, Wang Y, Mack WJ, Thompson PM, Schneider JA, Varkey J, Langen R, Mullins E, Jacobs RE, Zlokovic BV. Pericyte degeneration causes white matter dysfunction in the mouse central nervous system.. in Nature Medicine. 2018;24(3):326-337.
doi:10.1038/nm.4482 .

Montagne, Axel, Nikolakopoulou, Angeliki M, Zhao, Zhen, Sagare, Abhay P, Si, Gabriel, Lazic, Divna, Barnes, Samuel R, Daianu, Madelaine, Ramanathan, Anita, Go, Ariel, Lawson, Erica J, Wang, Yaoming, Mack, William J, Thompson, Paul M, Schneider, Julie A, Varkey, Jobin, Langen, Ralf, Mullins, Eric, Jacobs, Russell E, Zlokovic, Berislav V, "Pericyte degeneration causes white matter dysfunction in the mouse central nervous system." in Nature Medicine, 24, no. 3 (2018):326-337,
https://doi.org/10.1038/nm.4482 . .