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Immunology Jun 2018Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in... (Review)
Review
Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.
Topics: Adaptive Immunity; Aging; Animals; Blood-Brain Barrier; Central Nervous System; Environment; Humans; Immune Privilege; Immunity, Innate; Immunotherapy; Inflammation; Life Style; Microbiota; Neurodegenerative Diseases; Risk Factors
PubMed: 29513402
DOI: 10.1111/imm.12922 -
Stroke and Vascular Neurology Jul 2019The blood-brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement... (Review)
Review
The blood-brain barrier (BBB) is a highly complex and dynamic structure, mainly composed of brain microvascular endothelial cells, pericytes, astrocytes and the basement membrane (BM). The vast majority of BBB research focuses on its cellular constituents. Its non-cellular component, the BM, on the other hand, is largely understudied due to its intrinsic complexity and the lack of research tools. In this review, we focus on the role of the BM in BBB integrity. We first briefly introduce the biochemical composition and structure of the BM. Next, the biological functions of major components of the BM in BBB formation and maintenance are discussed. Our goal is to provide a concise overview on how the BM contributes to BBB integrity.
Topics: Animals; Basement Membrane; Blood-Brain Barrier; Capillary Permeability; Collagen Type IV; Extracellular Matrix Proteins; Heparan Sulfate Proteoglycans; Humans; Laminin; Membrane Glycoproteins; Signal Transduction
PubMed: 31338215
DOI: 10.1136/svn-2018-000198 -
Proceedings of the National Academy of... Apr 2020The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important...
The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.
Topics: Aged; Alzheimer Disease; Biological Transport; Blood-Brain Barrier; Brain; Drug Delivery Systems; Female; Hippocampus; Humans; Male; Microbubbles; Middle Aged; Ultrasonic Therapy; Ultrasonic Waves; Ultrasonography
PubMed: 32284421
DOI: 10.1073/pnas.2002571117 -
Peptides Oct 2015The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first... (Review)
Review
The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational molecules, informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiological changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaption goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system.
Topics: Animals; Blood-Brain Barrier; Humans; Peptides; Protein Transport
PubMed: 25805003
DOI: 10.1016/j.peptides.2015.03.010 -
Nature Nov 2010Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This...
Vascular endothelial cells in the central nervous system (CNS) form a barrier that restricts the movement of molecules and ions between the blood and the brain. This blood-brain barrier (BBB) is crucial to ensure proper neuronal function and protect the CNS from injury and disease. Transplantation studies have demonstrated that the BBB is not intrinsic to the endothelial cells, but is induced by interactions with the neural cells. Owing to the close spatial relationship between astrocytes and endothelial cells, it has been hypothesized that astrocytes induce this critical barrier postnatally, but the timing of BBB formation has been controversial. Here we demonstrate that the barrier is formed during embryogenesis as endothelial cells invade the CNS and pericytes are recruited to the nascent vessels, over a week before astrocyte generation. Analysing mice with null and hypomorphic alleles of Pdgfrb, which have defects in pericyte generation, we demonstrate that pericytes are necessary for the formation of the BBB, and that absolute pericyte coverage determines relative vascular permeability. We demonstrate that pericytes regulate functional aspects of the BBB, including the formation of tight junctions and vesicle trafficking in CNS endothelial cells. Pericytes do not induce BBB-specific gene expression in CNS endothelial cells, but inhibit the expression of molecules that increase vascular permeability and CNS immune cell infiltration. These data indicate that pericyte-endothelial cell interactions are critical to regulate the BBB during development, and disruption of these interactions may lead to BBB dysfunction and neuroinflammation during CNS injury and disease.
Topics: Animals; Blood-Brain Barrier; Cells, Cultured; Central Nervous System; Gene Expression Regulation, Developmental; Mice; Mice, Inbred C57BL; Mice, Knockout; Pericytes; Rats; Rats, Sprague-Dawley
PubMed: 20944625
DOI: 10.1038/nature09513 -
Current Opinion in Biotechnology Apr 2017Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency... (Review)
Review
Mammals require essential nutrients from dietary sources to support normal metabolic, physiological and neuronal functions, to prevent diseases of nutritional deficiency as well as to prevent chronic disease. Disease and/or its treatment can modify fundamental biological processes including cellular nutrient accretion, stability and function in cells. These effects can be isolated to a specific diseased organ in the absence of whole-body alterations in nutrient status or biochemistry. Loss of blood-brain barrier function, which occurs in in-born errors of metabolism and in chronic disease, can cause brain-specific folate deficiency and contribute to disease co-morbidity. The role of brain folate deficiency in neuropsychiatric disorders is reviewed, as well as emerging diagnostic and nutritional strategies to identify and address brain folate deficiency in blood-brain barrier dysfunction.
Topics: Blood-Brain Barrier; Diet; Folic Acid; Humans
PubMed: 28189938
DOI: 10.1016/j.copbio.2017.01.006 -
Bosnian Journal of Basic Medical... Sep 2022The blood-brain barrier (BBB) functions as a highly selective border of endothelial cells, protecting the central nervous system from potentially harmful substances by... (Review)
Review
The blood-brain barrier (BBB) functions as a highly selective border of endothelial cells, protecting the central nervous system from potentially harmful substances by selectively controlling the entry of cells and molecules, including components of the immune system. To study the BBB properties, find suitable therapies, and identify new drug targets, there is a need to develop representative in vitro BBB models. In this article, we describe the astrocyte roles in the BBB functioning and human in vitro BBB models.
Topics: Astrocytes; Blood Substitutes; Blood-Brain Barrier; Endothelial Cells; Humans
PubMed: 35366791
DOI: 10.17305/bjbms.2021.6943 -
Birth Defects Research Dec 2017The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the... (Review)
Review
The blood-brain barrier (BBB) serves as a gateway for passage of drugs, chemicals, nutrients, metabolites, and hormones between vascular and neural compartments in the brain. Here, we review BBB development with regard to the microphysiology of the neurovascular unit (NVU) and the impact of BBB disruption on brain development. Our focus is on modeling these complex systems. Extant in silico models are available as tools to predict the probability of drug/chemical passage across the BBB; in vitro platforms for high-throughput screening and high-content imaging provide novel data streams for profiling chemical-biological interactions; and engineered human cell-based microphysiological systems provide empirical models with which to investigate the dynamics of NVU function. Computational models are needed that bring together kinetic and dynamic aspects of NVU function across gestation and under various physiological and toxicological scenarios. This integration will inform adverse outcome pathways to reduce uncertainty in translating in vitro data and in silico models for use in risk assessments that aim to protect neurodevelopmental health.
Topics: Animals; Blood-Brain Barrier; Brain; Humans; Systems Biology; Toxicology
PubMed: 29251840
DOI: 10.1002/bdr2.1180 -
International Journal of Molecular... Jul 2021The blood-brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from... (Review)
Review
The blood-brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer's disease and Parkinson's disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.
Topics: Animals; Blood-Brain Barrier; Brain; Cerebrovascular Circulation; Humans; Induced Pluripotent Stem Cells; Models, Biological; Neurodegenerative Diseases
PubMed: 34299328
DOI: 10.3390/ijms22147710 -
Biochemical Society Transactions Apr 2023A healthy brain is protected by the blood-brain barrier (BBB), which is formed by the endothelial cells that line brain capillaries. The BBB plays an extremely important... (Review)
Review
A healthy brain is protected by the blood-brain barrier (BBB), which is formed by the endothelial cells that line brain capillaries. The BBB plays an extremely important role in supporting normal neuronal function by maintaining the homeostasis of the brain microenvironment and restricting pathogen and toxin entry to the brain. Dysfunction of this highly complex and regulated structure can be life threatening. BBB dysfunction is implicated in many neurological diseases such as stroke, Alzheimer's disease, multiple sclerosis, and brain infections. Among other mechanisms, inflammation and/or flow disturbances are major causes of BBB dysfunction in neurological infections and diseases. In particular, in ischaemic stroke, both inflammation and flow disturbances contribute to BBB disruption, leading to devastating consequences. While a transient or minor disruption to the barrier function could be tolerated, chronic or a total breach of the barrier can result in irreversible brain damage. It is worth noting that timing and extent of BBB disruption play an important role in the process of any repair of brain damage and treatment strategies. This review evaluates and summarises some of the latest research on the role of the BBB during neurological disease and infection with a focus on the effects of inflammation and flow disturbances on the BBB. The BBB's crucial role in protecting the brain is also the bottleneck in central nervous system drug development. Therefore, innovative strategies to carry therapeutics across the BBB and novel models to screen drugs, and to study the complex, overlapping mechanisms of BBB disruption are urgently needed.
Topics: Humans; Blood-Brain Barrier; Brain Ischemia; Endothelial Cells; Stroke; Nervous System Diseases; Inflammation
PubMed: 36929707
DOI: 10.1042/BST20220830