Cyclooxygenase‐2‐positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood–brain barrier

Fiala, Milan; Liu, Q. N.; Sayre, James W.; Pop, Viorela; Brahmandam, V.; Graves, Michael C.; Vinters, Harry V.

doi:10.1046/j.1365-2362.2002.00994.x

Cited by 259 publications

(221 citation statements)

References 64 publications

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“…These findings support previous studies demonstrating BBB damage in AD [12][13][14][15][16][17][18][19][20][21][22][23][24][25] and suggest that APOE genotype influences the degree of BBB damage. 15,17,[22][23][24] The present study extends, however, previous findings by showing that a greater BBB disruption in AD APOE4 compared with AD APOE3 carriers could be related at least, in part, to a greater loss of pericyte population that has been shown to lead to a small vessel disease and a chronic BBB breakdown in murine transgenic models [6][7][8][9] and is associated with BBB breakdown in human neurodegenerative disorders such as AD [10][11][12] and amyotrophic lateral sclerosis.…”

Section: Discussionsupporting

confidence: 92%

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Halliday

Rege

et al. 2015

J Cereb Blood Flow Metab

498

478

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The blood-brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer's disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA-MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

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Section: Discussionsupporting

confidence: 92%

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Halliday

Rege

et al. 2015

J Cereb Blood Flow Metab

498

478

View full text Add to dashboard Cite

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“…Mediators identified in the inflammatory process include vasoactive amines (histamine and serotonin), eicosanoids (metabolites of arachidonic acid, prostaglandins and leukotrienes), platelet aggregation factors, cytokines (interleukins and tumoral necrosis factor -TNF), kinins (bradykinin), and free oxygen radicals, among others (Czermak et al, 1998;Ohishi, 2000). These substances are produced by inflammatory cells such as polymorphonuclear leukocytes (neutrophils, eosinophils, basophils), endothelial cells, mast cells, macrophages, monocytes, and lymphocytes (Fiala et al, 2002).…”

Section: Chemical Aspects Of the Inflammatory Responsementioning

confidence: 99%

Mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of propolis: a brief review

Araújo

Libério

Guerra

et al. 2012

Rev. bras. farmacogn.

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Many biological properties have been attributed to various types of propolis, including anti-inflammatory, antimicrobial, antioxidant, antitumor, wound healing, and immunomodulatory activities. This article reviewed studies published that investigated the anti-inflammatory activity of propolis of different origins and/ or its isolated components, focusing on the mechanisms of action underlying this activity and also addressing some aspects of immunomodulatory effects. The search was performed of the following databases: PubMed, Science Direct, HighWire Press, Scielo, Google Academics, Research Gate and ISI Web of Knowledgement. The anti-inflammatory activity was associated with propolis or compounds such as polyphenols (flavonoids, phenolic acids and their esters), terpenoids, steroids and amino acids. CAPE is the most studied compounds. The main mechanisms underlying the anti-inflammatory activity of propolis included the inhibition of cyclooxygenase and consequent inhibition of prostaglandin biosynthesis, free radical scavenging, inhibition of nitric oxide synthesis, reduction in the concentration of inflammatory cytokines and immunosuppressive activity. Propolis was found to exert an antiinflammatory activity in vivo and in vitro models of acute and chronic inflammation and others studies, indicating its promising potential as anti-inflammatory agent of natural origin and as a source of chemical compounds for the development of new drugs.

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“…Besides, enhanced levels of PGE 2 , the major product of COX-2, have been detected in cerebrospinal fluid in patients with HAD; these enhanced levels were associated with severity of dementia (30). Moreover, COX-2-positive macrophages infiltrating the brain of patients with HIV-1 encephalitis were described (31). There is also increasing evidence that COX-2 is involved in the pathogenesis of other neurological disorders associated with inflammation, including ischemic brain injury or Alzheimer's disease (reviewed in Ref.…”

mentioning

confidence: 99%

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

Blanco

Álvarez

Fresno

et al. 2008

The Journal of Immunology

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Both the HIV-1 protein Tat and cyclooxygenase-2 (COX-2) have been involved in the neuropathogenesis associated with HIV-1 infection. However, the relationship among them has not been addressed. Here, we found that extracellular Tat was able to induce COX-2 mRNA and protein expression and PGE2 synthesis in astrocytoma cell lines and primary human astrocytes. Moreover, Tat induced COX-2 promoter transcription. Deletion of NF-κB sites of the promoter did not diminish Tat-dependent transcription. Interestingly, Tat did not induce NF-κB activity, suggesting that NF-κB was not necessary to control COX-2 transcription induced by Tat. In contrast, deletion or mutation of the NFAT and/or AP-1 site abrogated COX-2 induction by Tat. Moreover, Tat induced transcription of NFAT- and AP-1-dependent reporter genes. Transfection of a dominant negative c-Jun mutant protein, TAM-67, or of a dominant negative version of NFAT, efficiently blocked the induction of COX-2 promoter by Tat, confirming the requirement of both transcription factors. Moreover, Tat induced NFAT translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NFAT and AP-1 in COX-2 induction and PGE2 synthesis by Tat was corroborated by using pharmacological inhibitors of the NFΑΤ, ERK, and JNK pathways. In summary, our results indicate that HIV-1 Tat was able to induce COX-2 and PGE2 synthesis in astrocytic cells through an NFAT/AP-1-dependent mechanism.

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Cyclooxygenase‐2‐positive macrophages infiltrate the Alzheimer’s disease brain and damage the blood–brain barrier

Cited by 259 publications

References 64 publications

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Mechanisms of action underlying the anti-inflammatory and immunomodulatory effects of propolis: a brief review

Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells

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