Estrogen protects the blood–brain barrier from inflammation-induced disruption and increased lymphocyte trafficking

Sex differences have been widely reported in neuroinflammatory disorders, focusing on the contributory role of estrogen. The microvascular endothelium of the brain is a critical component of the blood–brain barrier (BBB) and it is recognized as a major interface for communication between the periphery and the brain. As such, the cerebral capillary endothelium represents an important target for the peripheral estrogen neuroprotective functions, leading us to hypothesize that estrogen can limit BBB breakdown following the onset of peripheral inflammation.Comparison of male and female murine responses to peripheral LPS challenge revealed a short-term inflammation-induced deficit in BBB integrity in males that was not apparent in young females, but was notable in older, reproductively senescent females. Importantly, ovariectomy and hence estrogen loss recapitulated an aged phenotype in young females, which was reversible upon estradiol replacement. Using a well-established model of human cerebrovascular endothelial cells we investigated the effects of estradiol upon key barrier features, namely paracellular permeability, transendothelial electrical resistance, tight junction integrity and lymphocyte transmigration under basal and inflammatory conditions, modeled by treatment with TNFα and IFNγ. In all cases estradiol prevented inflammation-induced defects in barrier function, action mediated in large part through up-regulation of the central coordinator of tight junction integrity, annexin A1. The key role of this protein was then further confirmed in studies of human or murine annexin A1 genetic ablation models.Together, our data provide novel mechanisms for the protective effects of estrogen, and enhance our understanding of the beneficial role it plays in neurovascular/neuroimmune disease.     

Circulating TGF-β1 does not cross the intact blood-brain barrier

Transforming growth factor-β (TGF-β) from the periphery can cross the disrupted blood-brain barrier (BBB) to exert neuroprotective effects on the brain. Here, we quantify its permeation across the normal mouse BBB. By high-performance liquid chromatography, we show that TGF-β₁ is stable in circulating blood but does not cross the intact BBB after intravenous injection any faster than the vascular marker ^99mTc-albumin. This poor rate of influx cannot be explained by rapid efflux out of the brain or lack of lipophilicity as measured by the octanol/buffer partition coefficient, although the hydrogen bonding potential was relatively high, consistent with poor penetration. Thus, the therapeutic potential of TGF-β₁ administered in blood is probably limited to situations in which the BBB has been disrupted.     

The stimulation of dendritic cells by amyloid beta 1–42 reduces BDNF production in Alzheimer’s disease patients

Dendritic cells (DCs), the main actors of immune responses and inflammation, may play a role in Alzheimer’s disease (AD). Recent studies demonstrate that monocyte-derived DCs (MDDCs), generated in vitro in the presence of amyloid β_1–42 peptide (Aβ_1–42), show a functional alteration and an increased production of inflammatory molecules. Accordingly, MDDCs from AD patients show a more pronounced pro-inflammatory profile than DCs obtained from control subjects. In this study, we aimed at further investigating DC role in AD. Thus, we analyzed the in vitro effect of Aβ_1–42 treatment on already differentiated DCs from AD patients, as compared to control subjects. We found that Aβ_1–42 significantly decreases the expression of brain-derived neurotrophic factor (BDNF) in DCs derived from AD patients but not from control subjects. Thus, possibly due to their Aβ-induced reduction of neurotrophic support to neurons, DCs from AD patients might contribute to brain damage by playing a part in Aβ-dependent neuronal toxicity.     

Inhibition of TNF-α protects in vitro brain barrier from ischaemic damage

Cerebral ischaemia, associated with neuroinflammation and oxidative stress, is known to perturb blood–brain barrier (BBB) integrity and promote brain oedema formation. Using an in vitro model of human BBB composed of brain microvascular endothelial cells and astrocytes, this study examined whether suppression of TNF-α, a potent pro-inflammatory cytokine, might attenuate ischaemia-mediated cerebral barrier damage. Radical decreases in transendothelial electrical resistance and concomitant increases in paracellular flux across co-cultures exposed to increasing periods of oxygen-glucose deprivation alone (0.5–20 h) or followed by 20 h of reperfusion (OGD ± R) confirmed the deleterious effects of ischaemic injury on cerebral barrier integrity and function which concurred with reductions in tight junction protein (claudin-5 and occludin) expressions. OGD ± R elevated TNF-α secretion, NADPH oxidase activity, O₂⁻ production, actin stress fibre formation, MMP-2/9 activities and apoptosis in both endothelial cells and astrocytes. Increases in MMP-2 activity were confined to its extracellular isoform and treatments with OGD + R in astrocytes where MMP-9 could not be detected at all. Co-exposure of individual cell lines or co-cultures to an anti-TNF-α antibody dramatically diminished the extent of OGD ± R-evoked oxidative stress, morphological changes, apoptosis, MMP-2/9 activities while improving the barrier function through upregulation of tight junction protein expressions. In conclusion, vitiation of the exaggerated release of TNF-α may be an important therapeutic strategy in preserving cerebral integrity and function during and following a cerebral ischaemic attack.     

Serum from interferon-β-1b-treated patients with early multiple sclerosis stabilizes the blood-brain barrier in vitro

Interferon-β (IFN-β) stabilizes the blood-brain barrier (BBB) in vitro. Here we investigated the effect of serum from 15 IFN-β-1b-treated multiple sclerosis (MS) patients on the permeability read-outs of small solutes in an in vitro BBB model consisting of human brain microvascular endothelial cells in co-culture with rat astrocytes. The addition of sera from IFN-β-treated patients resulted in a significantly (p?相似文献   

Commentary on “Alzheimer's disease drug development and the problem of the blood-brain barrier”

The perspective by Dr. William Pardridge entitled “Alzheimer's Disease Drug Discovery and the Problem of the Blood-Brain Barrier” makes a strong case for the imbalance in resource distribution to the drug-discovery and brain drug delivery processes, where the latter received less than 1% of the investment of the former. My own calculations are consistent with this striking imbalance. Dr. Pardridge predicts that current trials of passive immunity against β-amyloid peptide will likely fail, whereas past trials of active immunization exhibited trial-ending side effects, in part because of disruption of the integrity of the blood-brain barrier. To bring an assessment of the physiology of the blood-brain barrier and the brain delivery of drugs to the fore, several changes are needed in the way we perceive the problem, train our young scientists, organize research efforts, and incentivize reaching our common goals of effective drug therapy for Alzheimer's disease.     

Neuroprotective effects of statins against amyloid β-induced neurotoxicity

A growing body of evidence suggests that disruption of the homeostasis of lipid metabolism affects the pathogenesis of Alzheimer's disease(AD). In particular, dysregulation of cholesterol homeostasis in the brain has been reported to considerably increase the risk of developing AD. Thus, dysregulation of lipid homeostasis may increase the amyloid β(Aβ) levels by affecting amyloid precursor protein(APP) cleavage, which is the most important risk factor involved in the pathogenesis of AD. Previous research demonstrated that Aβ can trigger neuronal insulin resistance, which plays an important role in response to Aβ-induced neurotoxicity in AD. Epidemiological studies also suggested that statin use is associated with a decreased incidence of AD. Therefore, statins are believed to be a good candidate for conferring neuroprotective effects against AD. Statins may play a beneficial role in reducing Aβ-induced neurotoxicity. Their effect involves a putative mechanism beyond its cholesterol-lowering effects in preventing Aβ-induced neurotoxicity. However, the underlying molecular mechanisms of the protective effect of statins have not been clearly determined in Aβ-induced neurotoxicity. Given that statins may provide benefits beyond the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A(HMG-Co A) reductase, these drugs may also improve the brain. Thus, statins may have beneficial effects on impaired insulin signaling by activating AMP-activated protein kinase(AMPK) in neuronal cells. They play a potential therapeutic role in targeting Aβ-mediated neurotoxicity.     

The role of APOE-?4 and beta amyloid in the differential rate of recovery from ECT: a review

Individual biological differences may contribute to the variability of outcomes, including cognitive effects, observed following electroconvulsive treatment (ECT). A narrative review of the research literature on carriage of the apolipoprotein E ɛ4 allele (APOE-ɛ4) and the protein biomarker beta amyloid (Aβ) with ECT cognitive outcome was undertaken. ECT induces repeated brain seizures and there is debate as to whether this causes brain injury and long-term cognitive disruption. The majority of ECT is administered to the elderly (over age 65 years) with drug-resistant depression. Depression in the elderly may be a symptom of the prodromal stage of Alzheimer''s disease (AD). Carriage of the APOE-ɛ4 allele and raised cerebral Aβ are consistently implicated in AD, but inconsistently implicated in brain injury (and related syndromes) recovery rates. A paucity of brain-related recovery, genetic and biomarker research in ECT responses in the elderly was found: three studies have examined the effect of APOE-ɛ4 allele carriage on cognition in the depressed elderly receiving ECT, and two have examined Aβ changes after ECT, with contradictory findings. Cognitive changes in all studies of ECT effects were measured by a variety of psychological tests, making comparisons of such changes between studies problematic. Further, psychological test data-validity measures were not routinely administered, counter to current testing recommendations. The methodological issues of the currently available literature as well as the need for well-designed, hypothesis driven, longitudinal studies are discussed.     

High-frequency (50 Hz) electroacupuncture ameliorates cognitive impairment in rats with amyloid beta 1–42-induced Alzheimer's disease

Acupuncture has been shown to ameliorate cognitive impairment of Alzheimer’s disease.Acupoints and stimulation frequency influence the therapeutic effect of electroacupuncture.Rat models of Alzheimer’s disease were established by injecting amyloid beta 1–42(Aβ_(1–42))into the bilateral lateral ventricles.Electroacupuncture at 2,30,and 50 Hz was carried out at Baihui(GV20;15°obliquely to a depth of 2mm)and Shenshu(BL23;perpendicularly to 4–6 mm depth),once a day for 20 minutes(each),for 15 days,taking a break every 7 days.The Morris water maze test was conducted to assess the learning and memory.The expression levels of glycogen synthase kinase-3β(GSK-3β),p Ser9-GSK-3β,p Tyr216-GSK-3β,amyloid precursor protein and Aβ_(1–40) in the hippocampus were determined by western blot assay.Results demonstrated that electroacupuncture treatment at different frequencies markedly improved learning and memory ability,increased synaptic curvatures,decreased the width of synaptic clefts,thickened postsynaptic densities,and downregulated the expression of GSK-3β,amyloid precursor protein,and Aβ_(1–40).pSer9-GSK-3βexpression markedly decreased,while p Tyr216-GSK-3βexpression increased.High-frequency(50 Hz)electroacupuncture was more effective than low(2 Hz)or medium-frequency(30 Hz)electroacupuncture.In conclusion,electroacupuncture treatment exerts a protective effect against Aβ_(1–42)-induced learning and memory deficits and synapse-ultrastructure impairment via inhibition of GSK-3βactivity.Moreover,high-frequency electroacupuncture was the most effective therapy.     

7.0T nuclear magnetic resonance evaluation of the amyloid beta(1–40) animal model of Alzheimer's disease: comparison of cytology verification

3.0T magnetic resonance spectroscopic imaging is a commonly used method in the research of brain function in Alzheimer's disease.However,the role of 7.0T high-field magnetic resonance spectroscopic imaging in brain function of Alzheimer's disease remains unclear.In this study,7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer's disease rats,the N-acetylaspartate wave crest was reduced,and the creatine and choline wave crest was elevated.This finding was further supported by hematoxylin-eosin staining,which showed a loss of hippocampal neurons and more glial cells.Moreover,electron microscopy showed neuronal shrinkage and mitochondrial rupture,and scanning electron microscopy revealed small size hippocampal synaptic vesicles,incomplete synaptic structure,and reduced number.Overall,the results revealed that 7.0T high-field nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer's disease rats in vivo,allowing the possibility for assessing the success rate and grading of the amyloid beta(1–40) animal model of Alzheimer's disease.     

Are claudin-5 tight-junction proteins in the blood-brain barrier porous?

The capillaries of the brain are particularly special,as they are not simply conduits for blood,but are primarily responsible to ensure that the neurons function in a strictly regulated homeostatic interstitium.Brain endothelial cells(BECs)express a plethora of ion channels on its luminal and abluminal surfaces,namely:potassium(K^+)channels(i.e.,Kir2 and Kv1),chloride(Cl^)/bicarbonate(HCO3^–)channels,as well as a number of ion-solute exchangers(Redzic et al.,2011).     

Is the ischemic blood-brain barrier insufficiency responsible for full-blown Alzheimer's disease?

The goal of this paper is to provide scientists with a comprehensive review of the state-of-the-art influence the ischemic blood-brain barrier (BBB) has on the final development of Alzheimer's disease and to provide detailed food-for-thought which will hopefully stimulate more researchers in this area of neuroscience. Understanding new and fundamental concepts about the behavior of the BBB during long-term reperfusion after ischemia with a variety of new neuropathogenic factors can hopefully provide some interesting clues related to the pathologic processes issues that have been receiving considerable attention in the human clinic. We present the recent data to understand the role of the BBB in maturation of both diseases and try to differentiate between primary and secondary pathologic mechanisms. In conclusion, the neuropathogenesis of Alzheimer's disease involves an initial ischemic neuronal alterations leading to enhanced neuronal vulnerability to beta-amyloid peptide and the ischemic breakdown of the BBB with leakage of serum borne beta-amyloid peptide into brain parenchyma, activation of beta-amyloid peptide-dependent toxicity culminating in the formation of amyloid plaques and finally end in full-blown Alzheimer's disease. In summary, probably we have combined mechanism(s) of ischemia processes, ischemic and chronic BBB dysfunction and beta-amyloid peptide-dependent injury in pathology of neurodegeneration that is observed in Alzheimer's disease. We speculate that Alzheimer's disease may be caused by silent and sublethal ischemic episodes that attack and slowly steal the minds of its victims. Finally, our review proposes the ischemic BBB-dependent mechanism(s) that probably are responsible for full-blown Alzheimer's disease.     

Structure and function of the blood–brain barrier

Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood–brain barrier (BBB), blood–CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood–CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.     

Human induced pluripotent stem cell based in vitro models of the blood-brain barrier:the future standard?

<正>There is an urgent and tremendous need for human disease models in drug development in order to improve preclinical predictability.In the case of brain disorders drugs have to cross the blood-brain barrier(BBB)to enter the central nervous system(CNS).It was estimated that more than 95%of the drugs cannot cross the BBB.In the case of biopharmaceutics,it seems to be even more difficult for     

Intracellular biology of Alzheimer’s disease amyloid beta peptide

Strong evidence links excess production of a small peptide and the pathogenesis of Alzheimer’s disease (AD). Originally this peptide, beta-amyloid 42 (Aβ42), was assumed to be released by a pathogenic event; it is now well established that Aβ42 is released from cells during normal cellular metabolism of the Alzheimer amyloid precursor protein. Recently, in a series of surprising reports it was discovered that Aβ42 is produced intracellularly, and what might have been regarded first as a strange abnormality of a few selected cell lines has now been recognized as an important cellular pathway for Aβ production. Moreover, the differences between secretory and intracellular Aβ production might hold the clues for brain specificity and cellular mechanisms of AD pathogenesis.