Review
Neurosciences
Wenhao Huang, Qing Xia, Feifei Zheng, Xue Zhao, Fangliang Ge, Jiaying Xiao, Zijie Liu, Yingying Shen, Ke Ye, Dayong Wang, Yanze Li
Summary: The neurovascular unit (NVU) plays a crucial role in the pathological changes of Alzheimer's disease (AD), maintaining microenvironmental homeostasis and metabolic balance in the central nervous system. Microglia, an important component of the NVU, promote neuroinflammation, blood-brain barrier breakdown, and neurovascular uncoupling, leading to NVU impairment. In this review, we discuss the mechanisms of microglia-mediated NVU dysfunction in AD and advancements in therapeutic approaches targeting microglial function and NVU restoration. Furthermore, we highlight the future research focus on the role of pericytes in microglia-mediated NVU dysfunction in AD.
JOURNAL OF ALZHEIMERS DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Michelle A. A. Erickson, Tatyana Shulyatnikova, William A. A. Banks, Melvin R. R. Hayden
Summary: The blood-brain barrier (BBB) is a crucial interface separating the central nervous system from the rest of the body, and inflammation can cause significant ultrastructural changes in its components such as brain endothelial cells, pericytes, microglial cells, and astrocytes. This study induced inflammation in mice and found that it led to alterations in plasma membrane, microvesicle production, exosome formation, mitochondria, and transcytosis of brain endothelial cells, while pericytes, microglial cells, and astrocytes also exhibited abnormal morphology. In summary, inflammation disrupts the neurovascular unit morphology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Neurosciences
Masaaki Yoshikawa, Shin Aizawa, Ronald W. Oppenheim, Carol Milligan
Summary: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes muscle weakness and atrophy. Pathological changes in ALS not only affect motor neurons, but also occur in the neurovascular units. These changes happen prior to neuromuscular junction denervation.
EXPERIMENTAL NEUROLOGY
(2022)
Review
Neurosciences
Parand Zarekiani, Henrique Nogueira Pinto, Elly M. Hol, Marianna Bugiani, Helga E. de Vries
Summary: The neurovascular unit (NVU) is a highly organized multicellular system in the brain, consisting of neuronal, glial, and vascular cells. Dysfunctions of the NVU occur in various neurological disorders, but little is known about its function in leukodystrophies. Human induced pluripotent stem cells (hiPSC) offer a solution to overcome the limitations of studying leukodystrophies, providing a biologically relevant human context and preserving the patient's genetic background. This review focuses on the NVU function in leukodystrophies and the use of hiPSC-derived models to study neurovascular pathophysiology in these diseases.
FLUIDS AND BARRIERS OF THE CNS
(2022)
Review
Cell Biology
Tara M. Caffrey, Emily B. Button, Jerome Robert
Summary: The brain's high metabolic demands require an efficient vascular system to supply nutrients and oxygen, which is regulated by the neurovascular unit composed of neurons, glial and vascular cells. Changes in neurovascular unit functions in neurodegenerative diseases can impair neurovascular coupling, blood-brain barrier permeability, cerebral blood flow, and waste clearance. Advanced physiologically-relevant human models of the neurovascular unit are being developed using stem-cell derived organoids and vascularized organoids to better understand disease processes and potential therapeutic strategies. Continued innovation in engineering and design is necessary to create more complex models for studying neurovascular unit functionality.
NEURAL REGENERATION RESEARCH
(2021)
Review
Cell Biology
Yoshimichi Sato, Jaime Falcone-Juengert, Teiji Tominaga, Hua Su, Jialing Liu
Summary: The neurovascular unit (NVU) depicts the relationship between brain cells and the vascular structure, regulating cerebral blood flow and maintaining brain homeostasis. Dysregulation of the NVU is a key pathological feature underlying neurological disorders. Understanding NVU dysfunction and remodeling is crucial for targeted therapy design and relevant research progress.
Review
Immunology
Brandon C. Smith, Rachel A. Tinkey, Benjamin C. Shaw, Jessica L. Williams
Summary: The blood-brain barrier is a barrier with selective permeability that separates the periphery from the central nervous system. The neurovascular unit, consisting of multiple cells, regulates the permeability of the blood-brain barrier. Understanding the contributions of each member of the neurovascular unit can lead to novel methods for delivering neurotherapies to the central nervous system.
IMMUNOLOGICAL REVIEWS
(2022)
Article
Neurosciences
Parand Zarekiani, Marjolein Breur, Nicole I. Wolf, Helga E. de Vries, Marjo S. van der Knaap, Marianna Bugiani
Summary: The blood-brain barrier in the brain is crucial for maintaining brain function in neurological disorders. Dysfunction of the neurovascular unit in leukodystrophies leads to endothelial dysfunction and astrocytic abnormalities. These findings enhance understanding of the pathophysiology of rare diseases.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2021)
Article
Neurosciences
Tiantian Li, Dianyi Li, Qingyuan Wei, Minghong Shi, Jiakun Xiang, Ruiwei Gao, Chao Chen, Zhi-Xiang Xu
Summary: The neurovascular unit (NVU) is crucial for neurovascular coupling, which involves communication between neurons, glia, and vascular cells to regulate the supply of oxygen and nutrients based on neural activity. NVU cellular elements create a barrier separating the central nervous system from the peripheral system, maintaining homeostasis. In Alzheimer's disease, amyloid-beta deposition impairs NVU functions, accelerating disease progression. This article reviews the current understanding of NVU cellular elements and their roles in regulating blood-brain barrier integrity, focusing on Alzheimer's disease. It also discusses various approaches for in vivo imaging and targeting of NVU components.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Developmental Biology
Saptarshi Biswas, Sanjid Shahriar, Nicholas P. Giangreco, Panos Arvanitis, Markus Winkler, Nicholas P. Tatonetti, William J. Brunken, Tyler Cutforth, Dritan Agalliu
Summary: Mural cells regulate Lama2 through the Wnt/β-catenin pathway during central nervous system development, promoting neurovascular unit and barrier maturation.
Article
Biochemistry & Molecular Biology
Kotaro Sugimoto, Naoki Ichikawa-Tomikawa, Keisuke Nishiura, Yasuto Kunii, Yasuteru Sano, Fumitaka Shimizu, Akiyoshi Kakita, Takashi Kanda, Tetsuya Imura, Hideki Chiba
Summary: Our research found that 5-HT1A receptors are expressed in brain microvascular endothelial cells and mural cells in the normal prefrontal cortex, and that PKA is aberrantly activated in both cell types in the schizophrenic PFC. Additionally, serotonin/5-HT1A signaling enhances endothelial CLDN5 expression in BMVECs under two-dimensional co-culture conditions.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Neurosciences
Yuyao Li, Dongqiong Xiao, Xiaodong Wang
Summary: Ferroptosis plays an important role in glial cells, neurons, and pericytes in the central nervous system (CNS), and may contribute to CNS diseases. Certain drugs are potential therapeutic strategies for neurological diseases.
FRONTIERS IN NEUROSCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Luis O. Soto-Rojas, Mar Pacheco-Herrero, Paola A. Martinez-Gomez, B. Berenice Campa-Cordoba, Ricardo Apatiga-Perez, Marcos M. Villegas-Rojas, Charles R. Harrington, Fidel de la Cruz, Linda Garces-Ramirez, Jose Luna-Munoz
Summary: Alzheimer's disease is the most common neurodegenerative disease worldwide, characterized by neurofibrillary tangles and amyloid beta accumulation. Vascular risk factors may lead to dysregulation of the neurovascular unit, contributing to A beta accumulation and neurodegeneration. Therapeutic approaches targeting abnormal A beta levels have had limited success in improving cognition.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Neurosciences
Natalie Hudson, Matthew Campbell
Summary: The homeostatic balance of the brain and retina is maintained by the blood-brain and inner blood-retinal barrier, which are specialized barriers formed by interconnected endothelial cells with tight junctions. Disruption of the tight junction complex can lead to detrimental effects on brain and retinal pathology by allowing harmful substances to enter neural tissues.
FRONTIERS IN MOLECULAR NEUROSCIENCE
(2021)
Article
Hematology
Zheying Sun, Scott S. Kemp, Prisca K. Lin, Kalia N. Aguera, George E. Davis
Summary: The study shows that EC expression of k-RasV12 disrupts capillary assembly by excessive lumen formation, reduced pericyte recruitment, and basement membrane deposition.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Koen Veys, Zheng Fan, Moheb Ghobrial, Ann Bouche, Melissa Garcia-Caballero, Kim Vriens, Nadine Vasconcelos Conchinha, Aline Seuwen, Felix Schlegel, Tatiane Gorski, Melissa Crabbe, Paola Gilardoni, Raphaela Ardicoglu, Johanna Schaffenrath, Cindy Casteels, Gino De Smet, Ilse Smolders, Koen Van Laere, E. Dale Abel, Sarah-Maria Fendt, Aileen Schroeter, Joanna Kalucka, Anna Rita Cantelmo, Thomas Walchli, Annika Keller, Peter Carmeliet, Katrien De Bock
CIRCULATION RESEARCH
(2020)
Article
Cardiac & Cardiovascular Systems
Maarja A. Mae, Liqun He, Sofia Nordling, Elisa Vazquez-Liebanas, Khayrun Nahar, Bongnam Jung, Xidan Li, Bryan C. Tan, Juat Chin Foo, Amaury Cazenave-Gassiot, Markus R. Wenk, Yvette Zarb, Barbara Lavina, Susan E. Quaggin, Marie Jeansson, Chengua Gu, David L. Silver, Michael Vanlandewijck, Eugene C. Butcher, Annika Keller, Christer Betsholtz
Summary: Through single-cell RNA sequencing and other methods, the study revealed the transcriptional, morphological, and functional changes in brain endothelial cells in response to pericyte deficiency. Endothelial cells without pericyte contact maintain a BBB-specific gene expression profile and acquire a venous-shifted molecular pattern.
CIRCULATION RESEARCH
(2021)
Article
Oncology
Johanna Schaffenrath, Tania Wyss, Liqun He, Elisabeth Jane Rushing, Mauro Delorenzi, Flavio Vasella, Luca Regli, Marian Christoph Neidert, Annika Keller
Summary: The study characterized transcriptional alterations in endothelial cells of brain tumors, revealing deregulation of genes related to cell proliferation, angiogenesis, and extracellular matrix in GBM and BM vasculature. Dysfunction of genes defining the BBB and deregulated expression of genes in vessel-associated fibroblasts in GBM were also identified. These findings contribute to the development of drug delivery platforms and warrant further investigation into the cellular composition of brain tumor stroma.
Article
Multidisciplinary Sciences
Orsolya Toeroek, Bettina Schreiner, Johanna Schaffenrath, Hsing-Chuan Tsai, Upasana Maheshwari, Sebastian A. Stifter, Christina Welsh, Ana Amorim, Sucheta Sridhar, Sebastian G. Utz, Wiebke Mildenberger, Sina Nassiri, Mauro Delorenzi, Adriano Aguzzi, May H. Han, Melanie Greter, Burkhard Becher, Annika Keller
Summary: Pericytes regulate leukocyte infiltration in the adult central nervous system and play a role in neuroinflammation.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Yvette Zarb, Sucheta Sridhar, Sina Nassiri, Sebastian Guido Utz, Johanna Schaffenrath, Upasana Maheshwari, Elisabeth J. Rushing, K. Peter R. Nilsson, Mauro Delorenzi, Marco Colonna, Melanie Greter, Annika Keller
Summary: This study reveals the crucial role of microglia in vascular calcification within the neurovascular unit, with a specific activation phenotype termed calcification-associated microglia. Pharmacological ablation of microglia exacerbates vessel calcification, while microglia rely on functional TREM2 to control vascular calcification. These findings suggest a beneficial function of microglial activity in pathological vascular calcification and highlight a previously unrecognized role of microglia in halting the expansion of vascular calcification.
Article
Biology
Chaim Glueck, Kim David Ferrari, Noemi Binini, Annika Keller, Aiman S. Saab, Jillian L. Stobart, Bruno Weber
Summary: The study found that capillary pericytes exhibited irregular and higher frequency calcium signals, occurring in cellular microdomains, while smooth muscle cells and ensheathing pericytes showed similar calcium dynamics in vivo. Activation of neurons and acute elevation of extracellular potassium can suppress calcium activity in capillary pericytes.
Article
Neurosciences
Johanna Schaffenrath, Sheng-Fu Huang, Tania Wyss, Mauro Delorenzi, Annika Keller
Summary: Genetic variation in a population influences the manifestation of diseases, common lab mouse strains lack genetic variability in humans, brain vasculature functionality is crucial for brain diseases, BBB acts as a major obstacle for drug delivery into CNS.
FLUIDS AND BARRIERS OF THE CNS
(2021)
Article
Endocrinology & Metabolism
Elisa Vazquez-Liebanas, Khayrun Nahar, Giacomo Bertuzzi, Annika Keller, Christer Betsholtz, Maarja Andaloussi Mae
Summary: PDGFB expression in endothelial cells is critical for maintaining pericyte coverage and normal BBB function in adult quiescent microvasculature, but does not lead to vessel dilation, arterio-venous skewing, and microvascular calcification.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2022)
Review
Clinical Neurology
Menno R. Germans, Wenhua Sun, Martina Sebok, Annika Keller, Luca Regli, Menno R. Germans
Summary: The study conducted a systematic review on the molecular signature of bAVM-related hemorrhage, identifying several genetic polymorphisms and molecular pathways associated with an increased risk of bAVM rupture. Further investigation of these biomarkers and their relationship with noninvasive diagnostic methods is recommended for improved patient risk estimation and future treatment options.
WORLD NEUROSURGERY
(2022)
Review
Geriatrics & Gerontology
Upasana Maheshwari, Sheng-Fu Huang, Sucheta Sridhar, Annika Keller
Summary: Vascular calcifications refer to the ectopic deposition of calcium and phosphate in the blood vessels, often associated with pathological conditions. While peripheral organ vascular calcifications have been extensively studied, the understanding of vascular calcification in the central nervous system is limited. This review focuses on the occurrence of vessel calcifications in the brain in relation to aging and various brain diseases, using primary familial brain calcification as an example. The role of microglia in the brain's response to vessel calcification and their involvement in the clearance of calcifications are discussed.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Cell Biology
Stephanie K. Bonney, Vanessa Coelho-Santos, Sheng-Fu Huang, Marc Takeno, Joergen Kornfeld, Annika Keller, Andy Y. Shih
Summary: This article presents a meta-analysis of multiple data sets to explore the ultrastructural features of the cerebrovasculature. The analysis reveals diverse cell types and subcellular details, providing important insights into the functions of blood-brain barrier, blood flow control, brain clearance, and bioenergetics. The article also discusses the limitations and possible improvements of vascular segmentation and analysis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Article
Endocrinology & Metabolism
Jillian L. Stobart, Eva Erlebach, Chaim Glueck, Sheng-Fu Huang, Matthew Jp Barrett, Max Li, Sergei A. Vinogradov, Jan Klohs, Yvette Zarb, Annika Keller, Bruno Weber
Summary: This study found that deleting the PDGFB retention motif results in severe pericyte deficiency in the vascular network, leading to reduced cerebral vasodilation capacity and impaired oxygen delivery to the tissue. Pdgfb(ret/ret) mice also showed abnormal blood oxygen extraction, indicating a state of hypoxia. These findings suggest that severe pericyte deficiency can cause vascular abnormalities and altered cerebral blood flow, resembling arteriovenous malformations.
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
(2023)
Article
Medicine, Research & Experimental
Vasil Kecheliev, Leo Boss, Upasana Maheshwari, Uwe Konietzko, Annika Keller, Daniel Razansky, Roger M. Nitsch, Jan Klohs, Ruiqing Ni
Summary: The aim of this study is to investigate the neurovascular alterations, distribution and dislocation of aquaporin 4 (AQP4) associated with tau and amyloid-beta (Aβ) pathologies in Alzheimer's disease. The PR5 mouse model showed regional atrophy, preserved cerebral blood flow, reduced cerebral vessel density, and AQP4 dislocation and peri-tau enrichment in the hippocampus. On the other hand, the arcAβ mouse model showed cerebral microbleeds, reduced cerebral vessel density, cortical AQP4 dislocation, and cortical/hippocampal peri-plaque increases.
Article
Multidisciplinary Sciences
Xinhong Chen, Damien A. Wolfe, Dhanesh Sivadasan Bindu, Mengying Zhang, Naz Taskin, David Goertsen, Timothy F. Shay, Erin E. Sullivan, Sheng-Fu Huang, Sripriya Ravindra Kumar, Cynthia M. Arokiaraj, Viktor M. Plattner, Lillian J. Campos, John K. Mich, Deja Monet, Victoria Ngo, Xiaozhe Ding, Victoria Omstead, Natalie Weed, Yeme Bishaw, Bryan B. Gore, Ed S. Lein, Athena Akrami, Cory Miller, Boaz P. Levi, Annika Keller, Jonathan T. Ting, Andrew S. Fox, Cagla Eroglu, Viviana Gradinaru
Summary: Efficiently and specifically delivering genes across the brain vasculature remains a challenge for addressing neurological diseases. Researchers have modified adeno-associated virus (AAV9) capsids to transduce brain endothelial cells effectively in mice and rats. These modified AAVs also show superior transduction in non-human primates and ex vivo human brain slices, although the endothelial tropism is not conserved across species. The modified capsids can be used for serotype switching for sequential AAV administration in mice and genetically engineering the blood-brain barrier.
NATURE COMMUNICATIONS
(2023)
Article
Clinical Neurology
Upasana Maheshwari, Jose M. Mateos, Ulrike Weber-Stadlbauer, Ruiqing Ni, Virgil Tamatey, Sucheta Sridhar, Alejandro Restrepo, Pim A. de Jong, Sheng-Fu Huang, Johanna Schaffenrath, Sebastian A. Stifter, Flora Szeri, Melanie Greter, Huiberdina L. Koek, Annika Keller
Summary: Calcification of cerebral microvessels in the basal ganglia is a key feature of primary familial brain calcification (PFBC), a rare neurodegenerative disorder. Mutations in certain genes, including XPR1, have been identified to cause PFBC. This study shows that mice with heterozygous XPR1 mutations display reduced inorganic phosphate levels in the cerebrospinal fluid and age-related vascular calcifications in the thalamus.
