scholarly journals Age-associated physiological and pathological changes at the blood–brain barrier: A review

2016 ◽  
Vol 37 (1) ◽  
pp. 4-24 ◽  
Author(s):  
Franciska Erdő ◽  
László Denes ◽  
Elizabeth de Lange
Keyword(s):  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Neurovascular Unit ◽  
Developed Countries ◽  
Brain Barrier ◽  
Aging Brain ◽  
Pharmacoresistant Epilepsy ◽  
Morphological Alterations ◽  
Blood Brain ◽  
Junction Proteins

The age-associated decline of the neurological and cognitive functions becomes more and more serious challenge for the developed countries with the increasing number of aged populations. The morphological and biochemical changes in the aging brain are the subjects of many extended research projects worldwide for a long time. However, the crucial role of the blood–brain barrier (BBB) impairment and disruption in the pathological processes in age-associated neurodegenerative disorders received special attention just for a few years. This article gives an overview on the major elements of the blood–brain barrier and its supporting mechanisms and also on their alterations during development, physiological aging process and age-associated neurodegenerative disorders (Alzheimer's disease, multiple sclerosis, Parkinson's disease, pharmacoresistant epilepsy). Besides the morphological alterations of the cellular elements (endothelial cells, astrocytes, pericytes, microglia, neuronal elements) of the BBB and neurovascular unit, the changes of the barrier at molecular level (tight junction proteins, adheres junction proteins, membrane transporters, basal lamina, extracellular matrix) are also summarized. The recognition of new players and initiators of the process of neurodegeneration at the level of the BBB may offer new avenues for novel therapeutic approaches for the treatment of numerous chronic neurodegenerative disorders currently without effective medication.

Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction

2019 ◽  
Vol 11 (521) ◽  
pp. eaaw8283 ◽  
Author(s):  
Vladimir V. Senatorov ◽  
Aaron R. Friedman ◽  
Dan Z. Milikovsky ◽  
Jonathan Ofer ◽  
Rotem Saar-Ashkenazy ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Transforming Growth Factor ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Aging Brain ◽  
Tgfβ Signaling ◽  
Blood Brain ◽  
Tgfβ Receptors ◽  
Neural Dysfunction

Aging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the life span. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor–β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology in rodents. Specifically, infusion of the serum protein albumin into the young rodent brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors or pharmacological inhibition of TGFβ signaling reversed these symptomatic outcomes in aged mice. Last, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging and demonstrates that the aging brain may retain considerable latent capacity, which can be revitalized by therapeutic inhibition of TGFβ signaling.

scholarly journals Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction

2019 ◽  
Author(s):  
V.V. Senatorov ◽  
A.R. Friedman ◽  
D.Z. Milikovsky ◽  
J. Ofer ◽  
R. Saar-Ashkenazy ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Blood Brain Barrier ◽  
Transforming Growth Factor ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
Aging Brain ◽  
Tgfβ Signaling ◽  
Blood Brain ◽  
Tgfβ Receptors ◽  
Neural Dysfunction

AbstractAging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling.

Brain Drug Delivery: Overcoming the Blood-brain Barrier to Treat Tauopathies

2020 ◽  
Vol 26 (13) ◽  
pp. 1448-1465 ◽  
Author(s):  
Jozef Hanes ◽  
Eva Dobakova ◽  
Petra Majerova
Keyword(s):  
Drug Delivery ◽  
Blood Brain Barrier ◽  
Neurodegenerative Disorders ◽  
Brain Barrier ◽  
Neuronal Function ◽  
Brain Drug Delivery ◽  
Naturally Occurring ◽  
Blood Brain ◽  
Traditional Approaches ◽  
The Brain

Tauopathies are neurodegenerative disorders characterized by the deposition of abnormal tau protein in the brain. The application of potentially effective therapeutics for their successful treatment is hampered by the presence of a naturally occurring brain protection layer called the blood-brain barrier (BBB). BBB represents one of the biggest challenges in the development of therapeutics for central nervous system (CNS) disorders, where sufficient BBB penetration is inevitable. BBB is a heavily restricting barrier regulating the movement of molecules, ions, and cells between the blood and the CNS to secure proper neuronal function and protect the CNS from dangerous substances and processes. Yet, these natural functions possessed by BBB represent a great hurdle for brain drug delivery. This review is concentrated on summarizing the available methods and approaches for effective therapeutics’ delivery through the BBB to treat neurodegenerative disorders with a focus on tauopathies. It describes the traditional approaches but also new nanotechnology strategies emerging with advanced medical techniques. Their limitations and benefits are discussed.

scholarly journals Screening for Interacting Proteins with Peptide Biomarker of Blood–Brain Barrier Alteration under Inflammatory Conditions

2021 ◽  
Vol 22 (9) ◽  
pp. 4725
Author(s):  
Karina Vargas-Sanchez ◽  
Monica Losada-Barragán ◽  
Maria Mogilevskaya ◽  
Susana Novoa-Herrán ◽  
Yehidi Medina ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Specific Interaction ◽  
Brain Barrier ◽  
Mass Spectrometry Analysis ◽  
Peptide Ligand ◽  
Inflammatory Conditions ◽  
Blood Brain ◽  
Potential Biomarker

Neurodegenerative diseases are characterized by increased permeability of the blood–brain barrier (BBB) due to alterations in cellular and structural components of the neurovascular unit, particularly in association with neuroinflammation. A previous screening study of peptide ligands to identify molecular alterations of the BBB in neuroinflammation by phage-display, revealed that phage clone 88 presented specific binding affinity to endothelial cells under inflammatory conditions in vivo and in vitro. Here, we aimed to identify the possible target receptor of the peptide ligand 88 expressed under inflammatory conditions. A cross-link test between phage-peptide-88 with IL-1β-stimulated human hCMEC cells, followed by mass spectrometry analysis, was used to identify the target of peptide-88. We modeled the epitope–receptor molecular interaction between peptide-88 and its target by using docking simulations. Three proteins were selected as potential target candidates and tested in enzyme-linked immunosorbent assays with peptide-88: fibronectin, laminin subunit α5 and laminin subunit β-1. Among them, only laminin subunit β-1 presented measurable interaction with peptide-88. Peptide-88 showed specific interaction with laminin subunit β-1, highlighting its importance as a potential biomarker of the laminin changes that may occur at the BBB endothelial cells under pathological inflammation conditions.

scholarly journals Effects of cadmium on the glial architecture in lizard brain

2017 ◽  
Author(s):  
Rossana Favorito ◽  
Antonio Monaco ◽  
Maria C. Grimaldi ◽  
Ida Ferrandino
Keyword(s):  
Blood Brain Barrier ◽  
Glial Cells ◽  
Toxic Metal ◽  
Chemical Exposure ◽  
Brain Barrier ◽  
Cresyl Violet ◽  
Cytotoxic Action ◽  
Morphological Alterations ◽  
Blood Brain ◽  
The Brain

The glial cells are positioned to be the first cells of the brain parenchyma to face molecules crossing the blood-brain barrier with a relevant neuroprotective role from cytotoxic action of heavy metals on the nervous system. Cadmium is a highly toxic metal and its levels in the environment are increasing due to industrial activities. This element can pass the blood-brain barrier and have neurotoxic activity. For this reason we have studied the effects of cadmium on the glial architecture in the lizard Podarcis siculus, a significant bioindicator of chemical exposure due to its persistence in a variety of habitats. The study was performed on two groups of lizards. The first group of P. siculus was exposed to an acute treatment by a single i.p. injection (2 mg/kg-BW) of CdCl2 and sacrificed after 2, 7 and 16 days. The second one was used as control. The histology of the brain was studied by Hematoxylin/Eosin and Cresyl/Violet stains while the glial structures were analyzed by immunodetection of the glial fibrillary acidic protein (GFAP), the most widely accepted marker for astroglial cells. Evident morphological alterations of the brain were observed at 7 and 16 days from the injection, when we revealed also a decrease of the GFAP-immunopositive structures in particular in the rhombencephalic ventricle, telencephalon and optic tectum. These results show that in the lizards an acute exposure to cadmium provokes morphological cellular alterations in the brain but also a decrement of the expression of GFAP marker with possible consequent damage of glial cells functions.

scholarly journals Time-dependent dual effect of NLRP3 inflammasome in brain ischemia

2020 ◽  
Author(s):  
Alejandra Palomino-Antolin ◽  
Paloma Narros-Fernández ◽  
Víctor Farré-Alins ◽  
Javier Sevilla-Montero ◽  
Celine Decouty-Pérez ◽  
...  
Keyword(s):  
Brain Injury ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
Nlrp3 Inflammasome ◽  
Neurovascular Unit ◽  
Time Dependent ◽  
Brain Barrier ◽  
Dependent Manner ◽  
Dual Effect ◽  
Blood Brain

AbstractBackground and purposePost-ischemic inflammation contributes to worsening of ischemic brain injury and in this process, the inflammasomes play a key role. Inflammasomes are cytosolic multiprotein complexes which upon assembly activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischemic stroke remains controversial. Our aims were to determine the role of NLRP3 in ischemia and to explore the mechanism involved in the potential protective effect of the neurovascular unit.MethodsWT and NLRP3 knock-out mice were subjected to ischemia by middle cerebral artery occlusion (60 minutes) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.ResultsWe identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β, TNF-α), NLRP3 inflammasome components (NLRP3, pro-caspase-1), protease expression (MMP9) and endothelial adhesion molecules (ICAM, VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junctions proteins (ZO-1, Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.ConclusionsThese findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischemia with potential clinical translation.

scholarly journals Targeting microRNAs to Regulate the Integrity of the Blood–Brain Barrier

2021 ◽  
Vol 9 ◽  
Author(s):  
Juntao Wang ◽  
Fang Xu ◽  
Xiaoming Zhu ◽  
Xianghua Li ◽  
Yankun Li ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Cerebrovascular Diseases ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Brain Diseases ◽  
Blood Brain ◽  
Recent Developments ◽  
Important Regulator

The blood–brain barrier (BBB) is a highly specialized neurovascular unit that protects the brain from potentially harmful substances. In addition, the BBB also engages in the exchange of essential nutrients between the vasculature and brain parenchyma, which is critical for brain homeostasis. Brain diseases, including neurological disorders and cerebrovascular diseases, are often associated with disrupted BBB integrity, evidenced by increased permeability. Therefore, defining the mechanisms underlying the regulation of BBB integrity is crucial for the development of novel therapeutics targeting brain diseases. MicroRNAs (miRNA), a type of small non-coding RNAs, are emerging as an important regulator of BBB integrity. Here we review recent developments related to the role of miRNAs in regulating BBB integrity.

scholarly journals Interleukin-34 Restores Blood–Brain Barrier Integrity by Upregulating Tight Junction Proteins in Endothelial Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e115981 ◽  
Author(s):  
Shijie Jin ◽  
Yoshifumi Sonobe ◽  
Jun Kawanokuchi ◽  
Hiroshi Horiuchi ◽  
Yi Cheng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tight Junction ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tight Junction Proteins ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Blood Brain Barrier Integrity ◽  
Junction Proteins
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