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Nature Aging Mar 2021The blood-brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain... (Review)
Review
The blood-brain barrier (BBB) protects the central nervous system (CNS) from unregulated exposure to the blood and its contents. The BBB also controls the blood-to-brain and brain-to-blood permeation of many substances, resulting in nourishment of the CNS, its homeostatic regulation and communication between the CNS and peripheral tissues. The cells forming the BBB communicate with cells of the brain and in the periphery. This highly regulated interface changes with healthy aging. Here, we review those changes, starting with morphology and disruption. Transporter changes include those for amyloid beta peptide, glucose and drugs. Brain fluid dynamics, pericyte health and basement membrane and glycocalyx compositions are all altered with healthy aging. Carrying the allele leads to an acceleration of most of the BBB's age-related changes. We discuss how alterations in the BBB that occur with healthy aging reflect adaptation to the postreproductive phase of life and may affect vulnerability to age-associated diseases.
Topics: Blood-Brain Barrier; Amyloid beta-Peptides; Healthy Aging; Brain; Central Nervous System
PubMed: 34368785
DOI: 10.1038/s43587-021-00043-5 -
Fluids and Barriers of the CNS Sep 2022Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight... (Review)
Review
Mucopolysaccharidoses comprise a set of genetic diseases marked by an enzymatic dysfunction in the degradation of glycosaminoglycans in lysosomes. There are eight clinically distinct types of mucopolysaccharidosis, some with various subtypes, based on which lysosomal enzyme is deficient and symptom severity. Patients with mucopolysaccharidosis can present with a variety of symptoms, including cognitive dysfunction, hepatosplenomegaly, skeletal abnormalities, and cardiopulmonary issues. Additionally, the onset and severity of symptoms can vary depending on the specific disorder, with symptoms typically arising during early childhood. While there is currently no cure for mucopolysaccharidosis, there are clinically approved therapies for the management of clinical symptoms, such as enzyme replacement therapy. Enzyme replacement therapy is typically administered intravenously, which allows for the systemic delivery of the deficient enzymes to peripheral organ sites. However, crossing the blood-brain barrier (BBB) to ameliorate the neurological symptoms of mucopolysaccharidosis continues to remain a challenge for these large macromolecules. In this review, we discuss the transport mechanisms for the delivery of lysosomal enzymes across the BBB. Additionally, we discuss the several therapeutic approaches, both preclinical and clinical, for the treatment of mucopolysaccharidoses.
Topics: Blood-Brain Barrier; Child, Preschool; Glycosaminoglycans; Humans; Lysosomes; Mucopolysaccharidoses
PubMed: 36117162
DOI: 10.1186/s12987-022-00373-5 -
International Journal of Oral Science Jan 2023Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in...
Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer's disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.
Topics: Animals; Rats; Bacteremia; Blood-Brain Barrier; Caveolin 1; Gingipain Cysteine Endopeptidases; Permeability; Porphyromonas gingivalis; Transcytosis; Virulence Factors
PubMed: 36631446
DOI: 10.1038/s41368-022-00215-y -
Fluids and Barriers of the CNS Apr 2021The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via... (Review)
Review
The vessels of the central nervous system (CNS) have unique barrier properties. The endothelial cells (ECs) which comprise the CNS vessels contribute to the barrier via strong tight junctions, specific transporters, and limited endocytosis which combine to protect the brain from toxins and maintains brain homeostasis. Blood-brain barrier (BBB) leakage is a serious secondary injury in various CNS disorders like stroke, brain tumors, and neurodegenerative disorders. Currently, there are no drugs or therapeutics available to treat specifically BBB damage after a brain injury. Growing knowledge in the field of epigenetics can enhance the understanding of gene level of the BBB and has great potential for the development of novel therapeutic strategies or targets to repair a disrupted BBB. In this brief review, we summarize the epigenetic mechanisms or regulators that have a protective or disruptive role for components of BBB, along with the promising approaches to regain the integrity of BBB.
Topics: Blood-Brain Barrier; Central Nervous System Diseases; Epigenesis, Genetic; Gene Expression Regulation; Humans
PubMed: 33823899
DOI: 10.1186/s12987-021-00250-7 -
Annual Review of Biomedical Engineering Jul 2021The blood-brain barrier (BBB) is one of the most selective endothelial barriers. An understanding of its cellular, morphological, and biological properties in health and... (Review)
Review
The blood-brain barrier (BBB) is one of the most selective endothelial barriers. An understanding of its cellular, morphological, and biological properties in health and disease is necessary to develop therapeutics that can be transported from blood to brain. In vivo models have provided some insight into these features and transport mechanisms adopted at the brain, yet they have failed as a robust platform for the translation of results into clinical outcomes. In this article, we provide a general overview of major BBB features and describe various models that have been designed to replicate this barrier and neurological pathologies linked with the BBB. We propose several key parameters and design characteristics that can be employed to engineer physiologically relevant models of the blood-brain interface and highlight the need for a consensus in the measurement of fundamental properties of this barrier.
Topics: Biological Transport; Biology; Blood-Brain Barrier; Brain; Humans
PubMed: 34255993
DOI: 10.1146/annurev-bioeng-082120-042814 -
The FEBS Journal Feb 2022Brain homeostasis depends on the existence of the blood-brain barrier (BBB). Despite decades of research, the factors and signalling pathways for modulating and...
Brain homeostasis depends on the existence of the blood-brain barrier (BBB). Despite decades of research, the factors and signalling pathways for modulating and maintaining BBB integrity are not fully elucidated. Here, we characterise the expression and function of the multifunctional receptor, sortilin, in the cells of the BBB, in vivo and in vitro. We show that sortilin acts as an important regulatory protein of the BBB's tightness. In rats lacking sortilin, the BBB was leaky, which correlated well with relocated distribution of the localisation of zonula occludens-1, VE-cadherin and β-catenin junctional proteins. Furthermore, the absence of sortilin in brain endothelial cells resulted in decreased phosphorylation of Akt signalling protein and increased the level of phospho-ERK1/2. As a putative result of MAPK/ERK pathway activity, the junctions between the brain endothelial cells were disintegrated and the integrity of the BBB became compromised. The identified barrier differences between wild-type and Sort1-/- brain endothelial cells can pave the way for a better understanding of sortilin's role in the healthy and diseased BBB.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Blood-Brain Barrier; Cells, Cultured; Rats; Rats, Sprague-Dawley
PubMed: 34626084
DOI: 10.1111/febs.16225 -
Handbook of Experimental Pharmacology 2022The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is one of the characteristic hallmarks of Alzheimer's disease (AD). Aβ-peptide brain homeostasis is...
The accumulation of neurotoxic amyloid-beta (Aβ) in the brain is one of the characteristic hallmarks of Alzheimer's disease (AD). Aβ-peptide brain homeostasis is governed by its production and various clearance mechanisms. The blood-brain barrier provides a large surface area for influx and efflux mechanisms into and out of the brain. Different transporters and receptors have been implicated to play crucial roles in Aβ clearance from brain. Besides Aβ transport, the blood-brain barrier tightly regulates the brain's microenvironment; however, vascular alterations have been shown in patients with AD. Here, we summarize how the blood-brain barrier changes during aging and in disease and focus on recent findings of how the ABC transporter P-glycoprotein (ABCB1/P-gp) and the receptor low-density lipoprotein receptor-related protein 1 (LRP1) play a role in Aβ clearance from brain.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Blood-Brain Barrier; Brain; Humans; Peptide Fragments; Receptors, LDL
PubMed: 33580390
DOI: 10.1007/164_2020_418 -
Neurobiology of Disease Dec 2022The blood brain barrier (BBB) is a vital structure to protect the brain, tightly filtering the passage of nutrients and molecules from the blood to the brain. This is...
The blood brain barrier (BBB) is a vital structure to protect the brain, tightly filtering the passage of nutrients and molecules from the blood to the brain. This is critical for maintaining the proper functioning of the brain, and any disruption in the BBB has detrimental consequences often leading to diseases. It is not clear whether disruption of the BBB occurs first in depression or is the consequence of the disease, however disruption of the BBB has been observed in depressed patients and evidence points to the role of important culprits in depression, stress and inflammation in disrupting the integrity of the BBB. The mechanisms whereby stress, and inflammation affect the BBB remain to be fully understood. Yet, the role of cytokines in regulating tight junction protein expression seems crucial. Altogether, the findings in depression suggest that acting at the BBB level might provide therapeutic benefit in depression.
Topics: Humans; Blood-Brain Barrier; Depression; Inflammation; Biological Transport; Brain
PubMed: 36375722
DOI: 10.1016/j.nbd.2022.105926 -
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 -
Tissue Barriers Jan 2021Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host immune response attempting to eliminate the infection. After hospital discharge, half of... (Review)
Review
Sepsis is a life-threatening organ dysfunction triggered by a dysregulated host immune response attempting to eliminate the infection. After hospital discharge, half of the sepsis survivors recover, one-third of the patients die the following year, and one-sixth have a long-term cognitive impairment, including memory dysfunction, anxiety, depression, and post-traumatic stress disorder. The infection triggers the host immune response, and both can cause vascular endothelial damage, interrupting tight junctions proteins; consequently, the blood-brain barrier (BBB) breaks down, allowing and facilitating the entry of peripheral immune cells into the brain, which triggers or exacerbates the activation of glial cells and neuroinflammation. The focus of this review is to identify biochemical abnormalities induced by sepsis, which is associated with BBB dysfunction; provide evidence of biomarkers involved in the tight junction disruption and BBB damage, and draw attention to the role of the BBB as a bridge between systemic infection and brain inflammation.
Topics: Blood-Brain Barrier; Humans; Sepsis
PubMed: 33319634
DOI: 10.1080/21688370.2020.1840912