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Article ; Online: Safe and Effective Disease-Modifying Therapies for Small Blood Vessel Disease in the Brain.

Arboleda-Velasquez, Joseph F

2021 Volume 191, Issue 11, Page(s) 1852–1855

MeSH term(s)	Alzheimer Disease/therapy ; Animals ; Cerebral Small Vessel Diseases/therapy ; Humans
Language	English
Publishing date	2021-09-14
Publishing country	United States
Document type	Editorial
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2021.09.003
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Article ; Online: Notch Signaling in Vascular Endothelial and Mural Cell Communications.

O'Hare, Michael / Arboleda-Velasquez, Joseph F

Cold Spring Harbor perspectives in medicine

2022

Abstract: The Notch signaling pathway is a highly versatile and evolutionarily conserved mechanism with an important role in cell fate determination. Notch signaling plays a vital role in vascular development, regulating several fundamental processes such as ... ...

Abstract	The Notch signaling pathway is a highly versatile and evolutionarily conserved mechanism with an important role in cell fate determination. Notch signaling plays a vital role in vascular development, regulating several fundamental processes such as angiogenesis, arterial/venous differentiation, and mural cell investment. Aberrant Notch signaling can result in severe vascular phenotypes as observed in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and Alagille syndrome. It is known that vascular endothelial cells and mural cells interact to regulate vessel formation, cell maturation, and stability of the vascular network. Defective endothelial-mural cell interactions are a common phenotype in diseases characterized by impaired vascular integrity. Further refinement of the role of Notch signaling in the vascular junctions will be critical to attempts to modulate Notch in the context of human vascular disease. In this review, we aim to consolidate and summarize our current understanding of Notch signaling in the vascular endothelial and mural cells during development and in the adult vasculature.
Language	English
Publishing date	2022-05-09
Publishing country	United States
Document type	Journal Article
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a041159
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Article ; Online: Notch3 Signaling and Aggregation as Targets for the Treatment of CADASIL and Other NOTCH3-Associated Small-Vessel Diseases.

Schoemaker, Dorothee / Arboleda-Velasquez, Joseph F

The American journal of pathology

2021 Volume 191, Issue 11, Page(s) 1856–1870

Abstract: Mutations in the NOTCH3 gene can lead to small-vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations ... ...

Abstract	Mutations in the NOTCH3 gene can lead to small-vessel disease in humans, including the well-characterized cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a condition caused by NOTCH3 mutations altering the number of cysteine residues in the extracellular domain of Notch3. Growing evidence indicates that other types of mutations in NOTCH3, including cysteine-sparing missense mutations or frameshift and premature stop codons, can lead to small-vessel disease phenotypes of variable severity or penetrance. There are currently no disease-modifying therapies for small-vessel disease, including those associated with NOTCH3 mutations. A deeper understanding of underlying molecular mechanisms and clearly defined targets are needed to promote the development of therapies. This review discusses two key pathophysiological mechanisms believed to contribute to the emergence and progression of small-vessel disease associated with NOTCH3 mutations: abnormal Notch3 aggregation and aberrant Notch3 signaling. This review offers a summary of the literature supporting and challenging the relevance of these mechanisms, together with an overview of available preclinical experiments derived from these mechanisms. It highlights knowledge gaps and future research directions. In view of recent evidence demonstrating the relatively high frequency of NOTCH3 mutations in the population, and their potential role in promoting small-vessel disease, progress in the development of therapies for NOTCH3-associated small-vessel disease is urgently needed.
MeSH term(s)	Animals ; CADASIL/genetics ; CADASIL/metabolism ; CADASIL/pathology ; Cerebral Small Vessel Diseases/genetics ; Cerebral Small Vessel Diseases/metabolism ; Cerebral Small Vessel Diseases/pathology ; Humans ; Mutation ; Protein Aggregation, Pathological/genetics ; Protein Aggregation, Pathological/metabolism ; Protein Aggregation, Pathological/pathology ; Receptor, Notch3/genetics ; Receptor, Notch3/metabolism ; Signal Transduction/physiology
Chemical Substances	NOTCH3 protein, human ; Receptor, Notch3
Language	English
Publishing date	2021-04-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2021.03.015
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Article: APOE3

Perez-Corredor, Paula / Vanderleest, Timothy E / Vacano, Guido N / Sanchez, Justin S / Villalba-Moreno, Nelson D / Marino, Claudia / Krasemann, Susanne / Mendivil-Perez, Miguel A / Aguillón, David / Jiménez-Del-Río, Marlene / Baena, Ana / Sepulveda-Falla, Diego / Lopera, Francisco / Quiroz, Yakeel T / Arboleda-Velasquez, Joseph F / Mazzarino, Randall C

Frontiers in molecular neuroscience

2024 Volume 17, Page(s) 1373568

Abstract: A patient with ... ...

Abstract	A patient with the
Language	English
Publishing date	2024-03-20
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452967-9
ISSN	1662-5099
ISSN	1662-5099
DOI	10.3389/fnmol.2024.1373568
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Article ; Online: Isolation and Transfection of Primary Culture Bovine Retinal Pericytes.

Primo, Vincent A / Arboleda-Velasquez, Joseph F

Methods in molecular biology (Clifton, N.J.)

2016 Volume 1430, Page(s) 107–117

Abstract: This protocol describes an enzymatic approach for isolating homogeneous cultures of pericytes from retinas of bovine source. In summary, retinas are dissected, washed, digested, filtered, cultured in specific media to select for pericytes, and finally ... ...

Abstract	This protocol describes an enzymatic approach for isolating homogeneous cultures of pericytes from retinas of bovine source. In summary, retinas are dissected, washed, digested, filtered, cultured in specific media to select for pericytes, and finally expanded for a low passage culture of about 14 million bovine retinal pericytes (BRP) within 4-6 weeks. This protocol also describes a liposomal-based technique for transfection of BRPs.
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-3628-1_7
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Article ; Online: Clinical and research applications of magnetic resonance imaging in the study of CADASIL.

Schoemaker, Dorothee / Quiroz, Yakeel T / Torrico-Teave, Heirangi / Arboleda-Velasquez, Joseph F

Neuroscience letters

2019 Volume 698, Page(s) 173–179

Abstract: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited small vessel disease that leads to early cerebrovascular events and functional disability. It is the most common single-gene disorder ... ...

Abstract	Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is an inherited small vessel disease that leads to early cerebrovascular events and functional disability. It is the most common single-gene disorder leading to stroke. Magnetic resonance imaging (MRI) is a central component of the diagnosis and monitoring of CADASIL. Here we provide a descriptive review of the literature on three important aspects pertaining to the use of MRI in CADASIL. First, we review past research exploring MRI markers for this disease. Secondly, we describe results from studies investigating associations between neuroimaging abnormalities and neuropathology in CADASIL. Finally, we discuss previous findings relating MRI markers to clinical symptoms. This review thus provides a summary of the current state of knowledge regarding the use of MRI in CADASIL as well as suggestions for future research.
MeSH term(s)	Biomarkers ; Brain/pathology ; CADASIL/diagnosis ; CADASIL/pathology ; Humans ; Magnetic Resonance Imaging ; Neuroimaging ; Stroke/diagnosis ; Stroke/pathology
Chemical Substances	Biomarkers
Language	English
Publishing date	2019-01-08
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2019.01.014
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Article ; Online: Topical Nanoemulsion of a Runt-related Transcription Factor 1 Inhibitor for the Treatment of Pathologic Ocular Angiogenesis.

Delgado-Tirado, Santiago / Gonzalez-Buendia, Lucia / An, Miranda / Amarnani, Dhanesh / Isaacs-Bernal, Daniela / Whitmore, Hannah / Arevalo-Alquichire, Said / Leyton-Cifuentes, David / Ruiz-Moreno, Jose M / Arboleda-Velasquez, Joseph F / Kim, Leo A

Ophthalmology science

2022 Volume 2, Issue 3

Abstract: Purpose: To test the efficacy of runt-related transcription factor 1 (RUNX1) inhibition with topical nanoemulsion containing Ro5-3335 (eNano-Ro5) in experimental ocular neovascularization.: Design: Preclinical experimental study.: Participants: In ...

Abstract	Purpose: To test the efficacy of runt-related transcription factor 1 (RUNX1) inhibition with topical nanoemulsion containing Ro5-3335 (eNano-Ro5) in experimental ocular neovascularization. Design: Preclinical experimental study. Participants: In vitro primary culture human retinal endothelial cell (HREC) culture. C57BL/6J 6- to 10-week-old male and female mice. Methods: We evaluated the effect of eNano-Ro5 in cell proliferation, cell toxicity, and migration of HRECs. We used an alkali burn model of corneal neovascularization and a laser-induced model of choroidal neovascularization to test in vivo efficacy of eNano-Ro5 in pathologic angiogenesis in mice. We used mass spectrometry to measure penetration of Ro5-3335 released from the nanoemulsion in ocular tissues. Main outcome measures: Neovascular area. Results: RUNX1 inhibition reduced cell proliferation and migration in vitro. Mass spectrometry analysis revealed detectable levels of the active RUNX1 small-molecule inhibitor Ro5-3335 in the anterior and posterior segment of the mice eyes. Topical treatment with eNano-Ro5 significantly reduced corneal neovascularization and improved corneal wound healing after alkali burn. Choroidal neovascularization lesion size and leakage were significantly reduced after treatment with topical eNano-Ro5. Conclusions: Topical treatment with eNano-Ro5 is an effective and viable platform to deliver a small-molecule RUNX1 inhibitor. This route of administration offers advantages that could improve the management and outcomes of these sight-threatening conditions. Topical noninvasive delivery of RUNX1 inhibitor could be beneficial for many patients with pathologic ocular neovascularization.
Language	English
Publishing date	2022-04-20
Publishing country	Netherlands
Document type	Journal Article
ISSN	2666-9145
ISSN (online)	2666-9145
DOI	10.1016/j.xops.2022.100163
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Article ; Online: Cognitive performance in asymptomatic carriers of mutations R1031C and R141C in CADASIL.

Zuluaga-Castaño, Yesica / Montoya-Arenas, David Andrés / Velilla, Lina / Ospina, Carolina / Arboleda-Velasquez, Joseph F / Quiroz, Yakeel T / Lopera, Francisco

International journal of psychological research

2020 Volume 11, Issue 2, Page(s) 46–55

Abstract: CADASIL is the most common hereditary cause of repeated ischemic strokes, and has also been identified as a model of pure vascular dementia. The objective of this study was to establish the cognitive performance of asymptomatic carriers with the ... ...

Abstract	CADASIL is the most common hereditary cause of repeated ischemic strokes, and has also been identified as a model of pure vascular dementia. The objective of this study was to establish the cognitive performance of asymptomatic carriers with the mutations R1031C and R141C. This observational crosssectional analytical study divided subjects into three groups: asymptomatic carriers of the R1031C mutation ( = 39), asymptomatic carries of the R141C mutation ( = 8) and noncarriers ( = 50). Statistically significant differences were found ( < 0.05) between the group of the R1031C mutation and the noncarriers in constructional praxis, executive function and abstract reasoning. For the R141C mutation, scores below expected values in executive function and mental calculation were observed. It is concluded that asymptomatic carriers of the two mutations showed low performance in working memory, mental abstraction and processing speed, which could be associated with preclinical cognitive biomarkers preceding the presentation of the first vascular event.
Language	English
Publishing date	2020-05-31
Publishing country	Colombia
Document type	Journal Article
ZDB-ID	2620373-X
ISSN	2011-7922 ; 2011-2084
ISSN (online)	2011-7922
ISSN	2011-2084
DOI	10.21500/20112084.3373
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Article ; Online: Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection.

Henao-Restrepo, Julián / López-Murillo, Carolina / Valderrama-Carmona, Pablo / Orozco-Santa, Natalia / Gomez, Johana / Gutiérrez-Vargas, Johanna / Moraga, Renato / Toledo, Jorge / Littau, Jessica Lisa / Härtel, Steffen / Arboleda-Velásquez, Joseph F / Sepulveda-Falla, Diego / Lopera, Francisco / Cardona-Gómez, Gloria Patricia / Villegas, Andrés / Posada-Duque, Rafael

Brain pathology (Zurich, Switzerland)

2022 Volume 33, Issue 2, Page(s) e13119

Abstract: In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reactive response, ... ...

Abstract	In response to brain insults, astrocytes become reactive, promoting protection and tissue repair. However, astroglial reactivity is typical of brain pathologies, including Alzheimer's disease (AD). Considering the heterogeneity of the reactive response, the role of astrocytes in the course of different forms of AD has been underestimated. Colombia has the largest human group known to have familial AD (FAD). This group carries the autosomal dominant and fully penetrant mutation E280A in PSEN1, which causes early-onset AD. Recently, our group identified an E280A carrier who did not develop FAD. The individual was homozygous for the Christchurch mutation R136S in APOE3 (APOEch). Remarkably, APOE is the main genetic risk factor for developing sporadic AD (SAD) and most of cerebral ApoE is produced by astroglia. Here, we characterized astrocyte properties related to reactivity, glutamate homeostasis, and structural integrity of the gliovascular unit (GVU), as factors that could underlie the pathogenesis or protection of AD. Specifically, through histological and 3D microscopy analyses of postmortem samples, we briefly describe the histopathology and cytoarchitecture of the frontal cortex of SAD, FAD, and APOEch, and demonstrate that, while astrodegeneration and vascular deterioration are prominent in SAD, FAD is characterized by hyperreactive-like glia, and APOEch displays the mildest astrocytic and vascular alterations despite having the highest burden of Aβ. Notably, astroglial, gliovascular, and vascular disturbances, as well as brain cell death, correlate with the specific astrocytic phenotypes identified in each condition. This study provides new insights into the potential relevance of the gliovasculature in the development and protection of AD. To our knowledge, this is the first study assessing the components of the GVU in human samples of SAD, FAD, and APOEch.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Homozygote ; Mutation ; Brain/pathology ; Amyloid beta-Peptides/metabolism
Chemical Substances	Apolipoprotein E3 ; Amyloid beta-Peptides
Language	English
Publishing date	2022-09-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1051484-3
ISSN	1750-3639 ; 1015-6305
ISSN (online)	1750-3639
ISSN	1015-6305
DOI	10.1111/bpa.13119
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Article ; Online: Specific Abnormalities in White Matter Pathways as Interface to Small Vessels Disease and Cognition in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Individuals.

Jacobs, Heidi I L / Schoemaker, Dorothee / Torrico-Teave, Hei / Zuluaga, Yesica / Velilla-Jimenez, Lina / Ospina-Villegas, Carolina / Lopera, Francisco / Arboleda-Velasquez, Joseph F / Quiroz, Yakeel T

Brain connectivity

2021 Volume 12, Issue 1, Page(s) 52–60

Abstract: Background: ...

Abstract	Background:
MeSH term(s)	Brain/diagnostic imaging ; Brain/pathology ; CADASIL/complications ; CADASIL/diagnostic imaging ; CADASIL/genetics ; Cognition ; Diffusion Tensor Imaging ; Disease Progression ; Humans ; Leukoencephalopathies/complications ; Leukoencephalopathies/diagnostic imaging ; Leukoencephalopathies/genetics ; Magnetic Resonance Imaging ; White Matter/diagnostic imaging ; White Matter/pathology
Language	English
Publishing date	2021-06-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2609017-X
ISSN	2158-0022 ; 2158-0014
ISSN (online)	2158-0022
ISSN	2158-0014
DOI	10.1089/brain.2020.0980
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