P L McGeer

University of British Columbia - Vancouver, Vancouver, British Columbia, Canada

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Publications (586)2718.3 Total impact

  • Patrick L McGeer, Edith G McGeer
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    ABSTRACT: Introduction: Activated microglia are associated with the progression of Alzheimer's disease (AD), as well as many other neurodegenerative diseases of aging. Microglia are therefore key targets for therapeutic intervention. Areas covered: β-amyloid (Aβ) deposits activate the complement system, which, in turn, stimulates microglia to release neurotoxic materials. Research has focused primarily on anti-inflammatory agents to temper this toxic effect. More recently there has been a focus on converting microglia from this M1 state to an M2 state in which the toxic effects are reduced and their phagocytic activity toward Aβ enhanced. Studies in transgenic mice have suggested a number of possible anti-inflammatory approaches but they may not always be a good model. An example is vaccination with antibodies to Aβ, which is effective in mouse models, but has repeatedly failed in clinical trials. Biomarker studies indicate that AD commences many years prior to clinical onset. Expert opinion: A hopeful approach to a disease-modifying treatment of AD is to administer agents that inhibit the inflammatory stimulation of microglia or successfully convert them to an M2 state. However, any such treatment must be started early in the disease.
    Expert Opinion on Therapeutic Targets 11/2014; · 4.90 Impact Factor
  • Moonhee Lee, Edith McGeer, Patrick L McGeer
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    ABSTRACT: Neuroinflammation is hypothesized to be a major driving force behind Alzheimer's disease (AD) pathogenesis. This hypothesis predicts that activated microglial cells can stimulate neurons to produce excessive amounts of β-amyloid protein (Aβ1-42) and tau. The excess Aβ1-42 forms extracellular deposits which stimulate further microglial activation. The excess tau is partially released but also becomes phosphorylated forming intracellular neurofibrillary deposits. The end result is a positive feedback mechanism which drives the disease development. To test the viability of this hypothesis, we exposed differentiated SH-SY5Y and N-tera2/D1 (N-tera2) cells to conditioned medium (CM) from LPS/IFNγ-stimulated human microglia. We found that the CM caused a large increase in the production and release of Aβ and tau. The CM also caused SH-SY5Y cells to increase their expression of amyloid precursor protein and release of its β-secretase cleaved products (sAPPβs) as well as Aβ oligomers, but the CM reduced release of its α-secretase cleaved products (sAPPαs). Direct treatment of SH-SY5Y and N-tera2 cells with the inflammatory cytokines IL-6 and IL-1β as well as with Aβ1-42, resulted in an increase in tau messenger RNA and protein expression. Pretreatment of LPS/IFNγ-stimulated human microglia cells with the nonsteroidal anti-inflammatory drugs ibuprofen and aspirin, the antioxidant GSH, the H2S donor NaSH, and the anti-inflammatory cytokine IL-10, resulted in a CM with diminished ability to stimulate tau expression. There was no effect on the morphology of SH-SY5Y cells, or on their viability, following exposure to micromolar levels of Aβ1-42. Our data indicate that reactive microglia play an important role in governing the expression of Aβ and tau, and therefore the progression of AD. They provide further evidence that appropriate anti-inflammatory treatment should be beneficial in AD.
    Neurobiology of Aging 07/2014; · 4.85 Impact Factor
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    ABSTRACT: The properties of Ca2+ signaling mediated by purinergic receptors are intrinsically linked with functional activity of astrocytes. At present little is known concerning Ca2+-dependent purinergic responses in adult human astrocytes. This work has examined effects of purinergic stimulation to alter levels of intracellular Ca2+ in adult human astrocytes. Ca2+-sensitive spectrofluorometry was carried out to determine mobilization of intracellular Ca2+ following adenosine triphosphate (ATP) or 3[prime]-O-(4-benzoyl)benzoyl-ATP (Bz-ATP) stimulation of adult human astrocytes. In some experiments pharmacological modulation of Ca2+ pathways was applied to help elucidate mechanisms of Ca2+ signaling. RT-PCR was also performed to confirm human astrocyte expression of specific purinoceptors which were indicated from imaging studies. The endogenous P2 receptor agonist ATP (at 100 muM or 1 mM) applied in physiological saline solution (PSS) evoked a rapid increase of [Ca2+]i to a peak amplitude with the decay phase of response exhibiting two components. The two phases of decay consisted of an initial rapid component which was followed by a secondary slower component. In the presence of Ca2+-free solution, the secondary phase of decay was absent indicating this prolonged component was due to influx of Ca2+. This prolonged phase of decay was also attenuated with the store-operated channel (SOC) inhibitor gadolinium (at 2 muM) added to standard PSS, suggesting this component was mediated by SOC activation. These results are consistent with ATP activation of P2Y receptor (P2YR) in adult human astrocytes leading to respective rapid [Ca2+]i mobilization from intracellular stores followed by Ca2+ entry through SOC. An agonist for P2X7 receptor (P2X7R), BzATP induced a very different response compared with ATP whereby BzATP (at 300 muM) elicited a slowly rising increase in [Ca2+]i to a plateau level which was sustained in duration. The BzATP-induced increase in [Ca2+]i was not enhanced with lipopolysaccharide pre-treatment of cells as previously found for P2X7R mediated response in human microglia. RT-PCR analysis showed that adult human astrocytes in vitro constitutively express mRNA for P2Y1R, P2Y2R and P2X7R. These results suggest that activation of metabotropic P2YR (P2Y1R and/or P2Y2R) and ionotropic P2X7R could mediate purinergic responses in adult human astrocytes.
    BMC Neuroscience 01/2014; 15(1):18. · 2.85 Impact Factor
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    ABSTRACT: Paroxysmal nocturnal hemoglobinemia (PNH) is a rare but serious condition characterized by complement-mediated red blood cell (RBC) hemolysis and episodic thrombotic attack. It results from decay accelerating factor (CD55), and protectin (CD59), becoming attached to RBC and other cell surfaces. Absence of these protective proteins leaves such cells vulnerable to self attack at the C3 convertase and membrane attack complex (MAC) stages of complement activation. We have previously reported that aurin tricarboxylic acid (ATA) is an orally effective agent that selectively blocks complement activation at the C3 convertase stage as well as MAC formation at the C9 insertion stage. We used a CH50 assay method and western blot analysis to investigate the vulnerability to complement attack of PNH RBCs compared with normal RBCs. Zymosan was used as the activator of normal serum and PNH serum. ATA was added to the sera to determine the concentration necessary to protect the RBCs from lysis by the zymosan-activated sera. We found that erythrocytes from PNH patients on long term treatment with eculizumab were twice as vulnerable as normal erythrocytes to lysis induced by complement activated serum. Western blot data showed the presence of both C3 and C5 convertases on the PNH patient erythrocyte membranes. These data indicate persistent vulnerability of PNH erythrocytes to complement attack due to deficiencies in CD55 and CD59. ATA, when added to serum in vitro, protected PNH erythrocytes from complement attack, restoring their resistance to that of normal erythrocytes. We conclude that ATA, by protecting PNH erythrocytes from their decay accelerating factor (CD55) and protectin (CD59) deficiencies, may be an effective oral treatment in this disorder.
    PLoS ONE 01/2014; 9(1):e87316. · 3.53 Impact Factor
  • Patrick L McGeer, Edith G McGeer
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    ABSTRACT: The amyloid cascade hypothesis is widely accepted as the centerpiece of Alzheimer disease (AD) pathogenesis. It proposes that abnormal production of beta amyloid protein (Abeta) is the cause of AD and that the neurotoxicity is due to Abeta itself or its oligomeric forms. We suggest that this, in itself, cannot be the cause of AD because demonstrating such toxicity requires micromolar concentrations of these Abeta forms, while their levels in brain are a million times lower in the picomolar range. AD probably results from the inflammatory response induced by extracellular Abeta deposits, which later become enhanced by aggregates of tau. The inflammatory response, which is driven by activated microglia, increases over time as the disease progresses. Disease-modifying therapeutic attempts to date have failed and may continue to do so as long as the central role of inflammation is not taken into account. Multiple epidemiological and animal model studies show that NSAIDs, the most widely used antiinflammatory agents, have a substantial sparing effect on AD. These studies provide a proof of concept regarding the anti-inflammatory approach to disease modification. Biomarker studies have indicated that early intervention may be necessary. They have established that disease onset occurs more than a decade before it becomes clinically evident. By combining biomarker and pathological data, it is possible to define six phases of disease development, each separated by about 5 years. Phase one can be identified by decreases in Abeta in the CSF, phase 2 by increases of tau in the CSF plus clear evidence of Abeta brain deposits by PET scanning, phase 3 by slight decreases in brain metabolic rate by PET-FDG scanning, phase 4 by slight decreases in brain volume by MRI scanning plus minimal cognitive impairment, phase 5 by increased scanning abnormalities plus clinical diagnosis of AD, and phase 6 by advanced AD requiring institutional care. Utilization of antiinflammatory agents early in the disease process remains an overlooked therapeutic opportunity. Such agents, while not preventative, have the advantage of being able to inhibit the consequences of both Abeta and tau aggregation. Since there is more than a decade between disease onset and cognitive decline, a window of opportunity exists to introduce truly effective disease-modifying regimens. Taking advantage of this opportunity is the challenge for the future.
    Acta Neuropathologica 09/2013; · 9.78 Impact Factor
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    ABSTRACT: Hydrogen sulfide (H2 S) and nitric oxide (NO) have been described as gasotransmitters. Anti-inflammatory activity in the central and peripheral nervous systems may be one of their functions. Previously we demonstrated that several SH(-) donors including H2 S-releasing aspirin (S-ASA) exhibited anti-inflammatory and neuroprotective activity in vitro against toxins released by activated microglia and astrocytes. Here we report that NOSH-ASA, an NO- and H2 S-releasing hybrid of aspirin, has a significantly greater anti-inflammatory and neuroprotective effect than S-ASA or NO-ASA. When activated by LPS/IFNγ, human microglia and THP-1 cells release materials that are toxic to differentiated SH-SY5Y cells. These phenomena also occur with IFNγ-stimulated human astroglia and U373 cells. When the cells were treated with the S-ASA or NO-ASA, there was a significant enhancement of neuroprotection. However, NOSH-ASA had significantly more potent protection properties than NO-ASA or S-ASA. The effect was concentration-dependent, as well as incubation time-dependent. Such treatment not only reduced the release of the TNFα and IL-6, but also attenuated activation of P38 MAPK and NFκB proteins. All the compounds tested were not harmful when applied directly to SH-SY5Y cells. These data suggest that NOSH-ASA has significant anti-inflammatory properties and may be a new candidate for treating neurodegenerative disorders that have a prominent neuroinflammatory component such as Alzheimer disease and Parkinson disease. GLIA 2013.
    Glia 08/2013; · 5.47 Impact Factor
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    ABSTRACT: Immunohistochemical staining has been used to determine expression patterns of the angiogenic transcription factor, Ets-1, in the brains of Alzheimer's disease (AD) individuals. Brain tissue from non-demented controls showed little expression of Ets-1 whereas in AD brain tissue, Ets-1 was ubiquitously expressed in cortex and hippocampus. Double immunostaining with von Willerbrand factor demonstrated prominent Ets-1 intravascular immunoreactivity (ir) in AD cortical microvessels. In addition, Ets-1 also exhibited extravascular expression characterized by a diffuse pattern of Ets-1 ir in AD brain. Double staining also showed Ets-1 colocalization in microvasculature with the potent angiogenic agent, vascular endothelial growth factor. Cell-associated tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine with pro-angiogenic activity, was primarily associated with diffuse extravascular Ets-1 ir. Clusters of HLA-DR positive microglia, resident immune cells of brain which release TNF-α, were also localized with diffuse Ets-1. Intravascular Ets-1 ir was maximally co-localized with soluble amyloid-β peptide (Aβ), Aβ1-40, in microvasculature whereas diffuse extravascular Ets-1 ir appeared in proximity to Aβ plaques in brain parenchyma. Similar overall results were obtained for patterns of Ets-1 staining in AD hippocampal tissue. This work provides novel findings on expression of the angiogenic transcription factor, Ets-1, in vascular remodeling and its association with pro-angiogenic factors, reactive microglia, and Aβ deposition in AD brain.
    Journal of Alzheimer's disease: JAD 07/2013; · 3.61 Impact Factor
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    ABSTRACT: Although chromogranin A (CGA) is frequently present in Alzheimer's disease (AD), senile plaques associated with microglial activation, little is known about basic difference between CGA and fibrillar amyloid-β (fAβ) as neuroinflammatory factors. Here we have compared the interleukin-1β (IL-1β) production pathways by CGA and fAβ in microglia. In cultured microglia, production of IL-1β was induced by CGA, but not by fAβ. CGA activated both nuclear factor-κB (NF-κB) and pro-caspase-1, whereas fAβ activated pro-caspase-1 only. For the activation of pro-caspase-1, both CGA and fAβ needed the enzymatic activity of cathepsin B (CatB), but only fAβ required cytosolic leakage of CatB and the NLRP3 inflammasome activation. In contrast, fAβ induced the IL-1β secretion from microglia isolated from the aged mouse brain. In AD brain, highly activated microglia, which showed intense immunoreactivity for CatB and IL-1β, surrounded CGA-positive plaques more frequently than Aβ-positive plaques. These observations indicate differential pathways for the microglial IL-1β production by CGA and fAβ, which may aid in better understanding of the pathological significance of neuroinflammation in AD.
    Neurobiology of aging 07/2013; · 5.94 Impact Factor
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    ABSTRACT: Aberrant complement activation is known to exacerbate the pathology in a spectrum of degenerative diseases of aging. We previously reported that aurin tricarboxylic acid (ATA) is an orally effective agent which prevents formation of the membrane attack complex of complement. It inhibits C9 attachment to tissue bound C5b678 and thus prevents bystander lysis of host cells. In this study, we investigated the effects of ATA on the alternative complement pathway. We found that ATA prevented cleavage of the tissue bound properdin-C3b-Factor B complex into the active C3 convertase enzyme properdin-C3b-Factor Bb. This inhibition was reversed by adding Factor D to the serum. Using enzyme-linked immunosorbent type assays, we established that ATA binds directly to Factor D and C9 but not to properdin or other complement proteins. We conclude that ATA, by inhibiting at two stages of the alternative pathway, might be a particularly effective therapeutic agent in conditions such as macular degeneration, paroxysmal nocturnal hemoglobinemia, and rheumatoid arthritis, in which activation of the alternative complement pathway initiates self damage.
    Neurobiology of aging 11/2012; · 5.94 Impact Factor
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    ABSTRACT: The GABAergic system is the main inhibitory neurotransmitter system in the vertebrate brain. Although it is well established that the GABAergic system is affected in neuropsychiatric disorders, in Alzheimer's disease (AD) it has been considered to be relatively spared. In this study we describe the immunohistochemical localization of the main enzymes of the GABAergic system; glutamate decarboxylase 65 (GAD65), GAD67, and GABA transferase (GABAT) in human brain. In neocortex, hippocampus, basal ganglia, and cerebellum, GAD65 and GAD67 immunoreactivity were found in neuropil granules, possibly axonal boutons or terminals, and in a subset of small to midsized neurons. GAD65 preferentially stained neuropil granules, while GAD67 preferentially stained neuronal cell bodies. GABAT intensely labeled many types of neurons and glia cells. While GAD65 and GAD67 stained the cytoplasm of cells homogeneously, GABAT labeling appeared irregular and granular. GAD65 immunoreactivity of neurons and neuropil was severely reduced in AD middle temporal gyrus, hippocampus, and putamen as determined by fluorescence and light microscopic immunohistochemistry. Western blotting revealed a similar reduction of GAD65, but not GAD67, protein levels in the middle temporal gyrus of AD. Our results suggest that the GABAergic system is more severely affected in AD than previously reported. This deficit may contribute to AD pathogenesis by loss of GABAergic inhibitory activity.
    Journal of Alzheimer's disease: JAD 10/2012; · 3.61 Impact Factor
  • M. Lee, E. McGeer, P.L. McGeer
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    ABSTRACT: Astrocytes become activated in degenerative neurological diseases. In order to gain a greater understanding of the inflammatory factors released upon activation, we stimulated adult human astrocytes with interferon-gamma and examined the resultant conditioned medium (CM) for toxicity against differentiated human neuroblastoma SH-SY5Y cells. Cell death was measured by lactate dehydrogenase release assay. We then used various treatments of the media to determine the distribution and nature of the toxic components.Removal of interleukin-6 by a specific antibody reduced the toxicity by 22%. Blockade of proteases with an inhibitor cocktail reduced it by a further 22%. When oxygen-free radical production was blocked with NADPH oxidase inhibitors, the toxicity was reduced by 15.4%. When prostaglandin production was blocked by cyclooxygenase inhibitors, the toxicity of the CM was reduced by 14.5%. When glutamate was removed by treatment with glutamate decarboxylase, the toxicity was reduced by 10.3%. When the inhibitors were added together to the astrocyte culture, the total toxicity of the CM was reduced by 91%. This was in reasonable agreement with the 85.37% total obtained by adding the individual components. The data show that activated astrocytes release a specific combination of neurotoxic compounds. They suggest that effective anti-inflammatory treatment of such neurodegenerative diseases as Alzheimer’s disease, Parkinson’s disease and Amyotrophic lateral sclerosis could be improved by using an appropriate combination of anti-inflammatory agents instead of relying on any single agent.
    Neuroscience 10/2012; 229:164–175. · 3.33 Impact Factor
  • Alzheimer's and Dementia 07/2012; 8(4):P418. · 17.47 Impact Factor
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    Sadayuki Hashioka, Andis Klegeris, Patrick L McGeer
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    ABSTRACT: Increasing evidence shows that the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) possesses potent anti-inflammatory and immunomodulatory properties. It is tempting to evaluate the potential of SAHA as a therapeutic agent in various neuroinflammatory and neurodegenerative disorders. We examined the effects of SAHA on interferon (IFN)-γ-induced neurotoxicity of human astrocytes and on IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3 in human astrocytes. We also studied the effects of SAHA on the astrocytic production of two representative IFN-γ-inducible inflammatory molecules, namely IFN-γ-inducible T cell α chemoattractant (I-TAC) and intercellular adhesion molecule-1 (ICAM-1). SAHA significantly attenuated the toxicity of astrocytes activated by IFN-γ towards SH-SY5Y human neuronal cells. In the IFN-γ-activated astrocytes, SAHA reduced the STAT3 phosphorylation. SAHA also inhibited the IFN-γ-induced astrocytic production of I-TAC, but not ICAM-1. These results indicate that SAHA suppresses IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. Due to its anti-neurotoxic and anti-inflammatory properties, SAHA appears to have the therapeutic or preventive potential for a wide range of neuroinflammatory disorders associated with activated astrocytes.
    Journal of Neuroinflammation 05/2012; 9:113. · 4.90 Impact Factor
  • Sadayuki Hashioka, Andis Klegeris, Patrick L McGeer
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    ABSTRACT: We examined the effects of L-type calcium channel blockers (CCBs) on toxicity exerted by activated human astrocytes and microglia towards SH-SY5Y human neuronal cells. The CCBs nimodipine (NDP) and verapamil (VPM) both significantly suppressed toxic secretions from human astrocytes and astrocytoma U-373 MG cells that were induced by interferon (IFN)-γ. NDP also inhibited neurotoxic secretions of human microglia and monocytic THP-1 cells that were induced by the combination of lipopolysaccharide and IFN-γ. In human astrocytes, both NDP and VPM reduced IFN-γ-induced phosphorylation of signal transducer and activator of transcription (STAT) 3. They also inhibited the astrocytic production of IFN-γ-inducible T cell α chemoattractant (I-TAC). These results suggest that CCBs attenuate IFN-γ-induced neurotoxicity of human astrocytes through inhibition of the STAT3 signaling pathway. L-type CCBs, especially NDP, might be a useful treatment option for a broad spectrum of neurodegenerative diseases, including Alzheimer disease, where the pathology is believed to be exacerbated by neurotoxic glial activation.
    Neuropharmacology 05/2012; 63(4):685-91. · 4.82 Impact Factor
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    ABSTRACT: We have recently reported effects of Mg2+ to confer neuroprotection against toxicity of purinergic stimulated microglia and THP-1 monocytes. To examine mechanisms underlying neuroprotection, we have studied Mg2+ modulation of transient changes in intracellular Ca2+ ([Ca2+]i) in THP-1 cells induced by P2X7R agonist 2',3'-[benzoyl-4-benzoyl]-ATP (BzATP). Application of BzATP caused a rapid transient increase in [Ca2+]i followed by a prolonged component. The time course of the secondary slower phase was significantly reduced with Ca2+-free extracellular solution, with treatment of THP-1 cells by the P2X7R antagonist, oxATP or with exposure of cells to the store-operated channel (SOC) inhibitor, SKF96365. These results suggest that Ca2+ influx, mediated by both the P2X7R or by SOC, contribute to the slow component of [Ca2+]i. Treatment of THP-1 cells with 10 mMMg2+ was highly effective in reducing the time course of BzATP-induced Ca2+ decay; unlike the other modulatory protocols, Mg2+ markedly inhibited the amplitudes of slow and rapid components. In addition, acute application of Mg2+ during BzATP-induced responses elicited in the presence of either oxATP or SKF96365 to block respective P2X7R and SOC contributions, rapidly attenuated [Ca2+]i to baseline levels. Priming of cells with the inflammatory stimulus LPS/IFN-γ markedly enhanced the slower, but not rapid, phase of BzATP-induced [Ca2+]i with application of 10 mMMg2+ inhibiting both components of response. A model is proposed to account for BzATP stimulation of both ionotropic P2XR and metabotropic P2YR which provides a mechanistic basis for elevated Mg2+ anti-inflammatory and neuroprotective actions in inflamed brain.
    Brain research 03/2012; 1442:1-8. · 2.83 Impact Factor
  • Patrick L. McGeer
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    ABSTRACT: An Overview of Therapeutic Targets for Defeating Alzheimer's Disease Alzheimer disease can be defeated. There is an urgency given the estimated incidence of 20,000 new cases per day. The biochemical targets that need to be hit are aggregates of beta amyloid protein and tau. These targets are known to be vulnerable to suitable inhibitory agents although none have yet reached the bedside. Once powerful ones are put into practice Alzheimer disease will become as rare as polio is today. New candidates can be easily screened in vitro and validated in vivo by testing in transgenic mice. Numerous candidates have already met these criteria but have gone no further because of the high cost of clinical trials. They include blockers of production and aggregation of beta amyloid protein, agents that clear it from brain, and agents that block its inflammatory stimulation. Some are drugs that have long been in use for other applications and others are components of herbal medicines. The fact that they are cheap is a strong disincentive to embarking upon high cost clinical trials. Moreover, expensive regulatory testing of new agents is beyond the reach of basic scientists. Success in defeating Alzheimer disease requires intervention with suitable agents before the disease sets in. Many millions of beta amyloid protein deposits are found in the brains of Alzheimer cases upon autopsy, indicating that many thousands accumulate in their brains each day. Every one is a focus of inflammation. The elements necessary to defeat Alzheimer disease are now at hand. Early diagnosis is now possible. Genetic evidence and biomarkers such beta amyloid protein levels in brain, CSF and even saliva can indicate impending disease. Promising agents have been identified. Skilled clinicians with desperate patients are available. These elements need to be combined in a series of clinical trials where changes in biochemical markers are followed. Funding of a collaborative consortium much akin to the Manhattan project which ended world war II is needed. Leaders with the differing skills required to take basic science discoveries to the bedside need to work together for the first time. As with the Manhattan project, Governments must step in to provide the necessary funds.
    American Association for the Advancement of Science 2012 Annual Meeting; 02/2012
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    ABSTRACT: Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC(50)) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs.
    Neurobiology of aging 01/2012; 33(10):2237-46. · 5.94 Impact Factor
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    ABSTRACT: Previous studies indicate that astrocytes are the brain cells that express acidic fibroblast growth factor (aFGF) and that the expression is increased upon activation. However, there has been no study investigating the significance of this phenomenon. Here we report that aFGF treatment of IFNγ-stimulated human astrocytes, and LPS/IFNγ-stimulated human microglia, enhances their secretion of inflammatory cytokines and other materials toxic to human neuroblastoma SH-SY5Y cells. The mechanism of aFGF enhancement involves stimulation of the receptor FGFR2 IIIb. We show by RT-PCR that this receptor, but not other FGF receptors, is robustly expressed by astrocytes and microglia. We establish by Western blotting, and immunohistochemistry on postmortem human brain tissue that the FGFR2 IIIb protein is expressed by both of these glial cell types. We blocked the inflammatory stimulant action of aFGF by transfecting microglia and astrocytes with a small inhibitory RNA (siRNA) to FGFR2 IIIb as well as by removal of aFGF using an anti-aFGF antibody. Treatment with bFGF in combination with the stimulants was without effect, but together with aFGF, it partially counteracted the action of aFGF, indicating that it may be a weak antagonist of FGFR2 IIIb. The inflammatory effect was also attenuated by treatment with inhibitors of protein kinase C, Src tyrosine kinase, and MEK-1/2 indicating the involvement of these intracellular pathways. Our data suggest that inhibition of expression or release of aFGF could have therapeutic potential by inhibiting inflammation in neurodegenerative diseases such as Alzheimer disease where many neuroinflammatory molecules are prominently expressed.
    Journal of Biological Chemistry 12/2011; 286(48):41230-45. · 4.60 Impact Factor
  • Claudia Schwab, Sheng Yu, Patrick L McGeer
    Acta Neuropathologica 11/2011; 123(2):289-92. · 9.78 Impact Factor
  • Claudia Schwab, Sheng Yu, Edith G McGeer, Patrick L McGeer
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    ABSTRACT: Optineurin mutations cause adult-onset primary open-angle glaucoma and have been associated with some familial forms of amyotrophic lateral sclerosis (ALS). Optineurin is involved in many cellular processes and interacts with a variety of proteins, among them huntingtin (htt). Here we report that in Huntington's disease (HD) cortex, optineurin frequently occurs in neuronal intranuclear inclusions, and to a lesser extent, in inclusions in the neuropil and in perikarya. Most intranuclear optineurin-positive inclusions were co-labeled for ubiquitin, but they were only occasionally and more weakly co-labeled for htt. Optineurin-labeled neuropil and perikaryal inclusions were commonly co-labeled for ubiquitin and htt. Although these inclusions were common in cortex, they were rare in striatum. Our results show that in HD optineurin is present in intranuclear, neuropil and perikaryal inclusions. It is not clear whether this indicates a primary involvement in the disease process. In HD, the known interaction of htt and optineurin may suggest that a different process takes place as compared to other neurodegenerative disorders.
    Neuroscience Letters 11/2011; 506(1):149-54. · 2.06 Impact Factor

Publication Stats

28k Citations
2,718.30 Total Impact Points


  • 1963–2014
    • University of British Columbia - Vancouver
      • • Department of Psychiatry
      • • Department of Anesthesiology, Pharmacology and Therapeutics
      • • Division of Neurology
      Vancouver, British Columbia, Canada
  • 2013
    • Mahidol University
      • Department of Pharmacology
      Bangkok, Bangkok, Thailand
  • 2010
    • Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
      Shanghai, Shanghai Shi, China
  • 2008
    • University of British Columbia - Okanagan
      Kelowna, British Columbia, Canada
  • 2006
    • University of Pennsylvania
      Philadelphia, Pennsylvania, United States
  • 1987–2002
    • Kyoto University
      • Department of Neurology
      Kyoto, Kyoto-fu, Japan
  • 2001
    • University College London
      • Institute of Neurology
      London, ENG, United Kingdom
  • 2000
    • Banner Sun Health Research Institute
      Sun City, Arizona, United States
    • University of Michigan
      • Department of Pharmacology
      Ann Arbor, MI, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • National Taiwan University
      T’ai-pei, Taipei, Taiwan
  • 1990–2000
    • Shiga University of Medical Science
      • • Department of Pediatrics
      • • Institute of Molecular Neurobiology
      Ōtsu-shi, Shiga-ken, Japan
  • 1997
    • University of Louisville
      • Department of Psychiatry and Behavioral Sciences
      Louisville, KY, United States
  • 1996
    • Institute for Neurodegenerative Disorders
      New Haven, Connecticut, United States
  • 1994
    • Chiba University
      • Department of Neurology
      Chiba-shi, Chiba-ken, Japan
  • 1991
    • Simon Fraser University
      Burnaby, British Columbia, Canada
  • 1989
    • Southern Illinois University School of Medicine
      • Department of Psychiatry
      Springfield, IL, United States
  • 1988
    • Kanazawa University
      • School of Medicine
      Kanazawa, Ishikawa, Japan
    • Jichi Medical University
      • Division of Anatomy
      Totigi, Tochigi, Japan
  • 1983
    • University of Victoria
      Victoria, British Columbia, Canada