Jian-Ping Guo

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

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Publications (11)57.37 Total impact

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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: 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
  • Jian-Ping Guo, Sheng Yu, Patrick L McGeer
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    ABSTRACT: Compounds that will inhibit buildup of amyloid-beta(Abeta) deposits in Alzheimer's disease (AD) brain are potential therapeutic agents. Here we report the development of two simple in vitro screening assays to identify such agents. We use these assays to evaluate the relative potency of some possible candidates. One assay is based on binding of fluorescence-tagged Abeta{1-42} to synthetic Abeta{1-42} plated in wells of fluorescent black-wall microplates. Fluorescence-tagged Abeta{1-42} solutions with and without blockers are then added to the plates, and the amount of bound fluorescence is measured. Another is a tissue type assay, where sections of unfixed AD or AD model transgenic mouse brains are mounted on glass slides. The same solutions assayed in the microplate test are then added to tissue sections. Binding of fluorescence-tagged Abeta{1-42} to the Abeta deposits in AD or transgenic brain tissue is detected with a fluorescence microscope. Good agreement is obtained between the two methods. Most of the tested agents have too low an affinity for Abeta {1-42} to be effective clinically. Agents that may have marginal affinity according to these tests include 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose (PGG), S-diclofenac, epigallocatechin gallate (EGCG), resveratrol, and extracts of spirulina, ginger, rhubarb, cinnamon, blueberries, and turmeric. Compounds which failed to show binding include scyllo-inositol, myo-inositol, rhamnose, ginkgolide A, emodin, rhein, caryophellene, curcumin, valproic acid, tramiprosate, and garlic extract.
    Journal of Alzheimer's disease: JAD 01/2010; 19(4):1359-70. · 4.17 Impact Factor
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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been identified in families with autosomal dominant late-onset Parkinson disease (PD). Lrrk2 is a phylogenetically conserved, ubiquitous protein, which is constitutively expressed in various cells including neurons and glial cells of human brain. We recently reported that Lrrk2 is identified in Lewy bodies in PD as well as in neuronal and glial inclusions in several other neurodegenerative disorders. Here we show that Lrrk2 is closely associated with the tau-positive inclusions in eight members of a family with frontotemporal dementia of the pallido-ponto-nigral degeneration type linked to the chromosome 17 N279K tau mutation (N279K/FTDP-17/PPND). Lrrk2 is colocalized with tau in oligodendroglial coiled bodies and intracytoplasmic neuronal inclusions. HLA-DR positive reactive microglia and ICAM-1 positive reactive astrocytes accumulated in affected areas demonstrating that inflammatory processes are also involved in the disease pathogenesis. Western blot analysis of soluble extracts of N279K/FTDP-17/PPND brain tissue suggests that C-terminal fragment(s) of apparent 64-75 kDa molecular weight may be the major Lrrk2 species in pathological deposits. The possibility that Lrrk2 is linked with various neurodegenerative disorders through the ubiquitin proteosome pathway is discussed. The results indicate that Lrrk2 is linked to frontotemporal atrophy of PPND type caused by N279K tau mutation. They also show that chronic inflammation is involved in the pathogenesis of N279K/FTDP-17/PPND.
    Acta Neuropathologica 10/2007; 114(3):243-54. · 9.73 Impact Factor
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    ABSTRACT: alpha-Synuclein, a gene whose mutations, duplication, and triplication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant alpha-synuclein has been attributed to date largely to faster formation of alpha-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) alpha-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated alpha-synuclein could activate microglia more powerfully than WT alpha-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that alpha-synuclein with the A30P or A53T mutations caused greater microglial activation than WT alpha-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant alpha-synuclein. Mutant alpha-synuclein also induced greater production of reactive oxygen species than WT alpha-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than alpha-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant alpha-synuclein.
    Glia 09/2007; 55(11):1178-88. · 5.07 Impact Factor
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    ABSTRACT: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal-dominant late-onset Parkinson disease. We report that by reverse transcriptase-polymerase chain reaction, the mRNA of LRRK2 is expressed in soluble extracts of human brain, liver, and heart and in cultured human astrocytes, microglia, and oligodendroglia as well as in human neuroblastoma cell lines. We find by Western blotting using a polyclonal antibody of the leucine-rich repeat kinase 2 protein (Lrrk2) specific for C-terminal residues 2,511-2,527 that an apparent full-length protein and several of its fractions are expressed in soluble extracts of normal human brain. By immunocytochemistry, the antibody recognizes neurons, and more weakly astrocytes and microglia, in normal brain tissue. It intensely labels Lewy bodies in Parkinson disease and related neurodegenerative disorders. It also labels a subset of neurofibrillary tangles in Alzheimer disease and the Parkinsonism dementia complex of Guam (PDCG). It labels thorn-shaped astrocytes and oligodendroglial coiled bodies in PDCG; oligodendroglial inclusions in multiple system atrophy; Pick bodies in Pick disease; nuclear and cytoplasmic inclusions in Huntington disease; and intraneuronal and glial inclusions in amyotrophic lateral sclerosis. In summary, LRRK2 is constitutively expressed in neurons and also in glial cells of human brain. It strongly associates with pathological inclusions in several neurodegenerative disorders.
    Journal of Neuropathology and Experimental Neurology 11/2006; 65(10):953-63. · 4.35 Impact Factor
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    ABSTRACT: To date, there is no reasonable explanation as to why plaques and tangles simultaneously accumulate in Alzheimer's disease (AD). We demonstrate here by Western blotting and ELISA that a stable complex can form between tau and amyloid-beta protein (Abeta). This complex enhances tau phosphorylation by GSK3beta, but the phosphorylation then promotes dissociation of the complex. We have localized the sites of this interaction by using peptide membrane arrays. Abeta binds to multiple tau peptides, especially those in exons 7 and 9. This binding is sharply reduced or abolished by phosphorylation of specific serine and threonine residues. Conversely, tau binds to multiple Abeta peptides in the mid to C-terminal regions of Abeta. This binding is also significantly decreased by GSK3beta phosphorylation of tau. We used surface plasmon resonance to determine the binding affinity of Abeta for tau and found it to be in the low nanomolar range and almost 1,000-fold higher than tau for itself. In soluble extracts from AD and control brain tissue, we detected Abeta bound to tau in ELISAs. We also found by double immunostaining of AD brain tissue that phosphorylated tau and Abeta form separate insoluble complexes within the same neurons and their processes. We hypothesize that in AD, an initial step in the pathogenesis may be the intracellular binding of soluble Abeta to soluble nonphosphorylated tau, thus promoting tau phosphorylation and Abeta nucleation. Blocking the sites where Abeta initially binds to tau might arrest the simultaneous formation of plaques and tangles in AD.
    Proceedings of the National Academy of Sciences 03/2006; 103(6):1953-8. · 9.81 Impact Factor
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    ABSTRACT: Thrombin is a serine protease that is generated by proteolytic cleavage of its precursor, prothrombin. We previously showed that thrombin proteolyses the microtubule-associated protein tau and that phosphorylation of tau inhibits this process. To characterize further the role of thrombin in the brain, we investigated prothrombin and thrombin expression in cultured brain cells and in brains of control, Alzheimer disease (AD) and parkinsonism-dementia complex of Guam (PDCG). We show by reverse transcriptase-polymerase chain reaction that prothrombin mRNA is expressed in brain tissues, neuroblastoma cells, and cultured human astrocytes, oligodendrocytes, and microglial cells. We also show by immunohistochemistry that the proteins prothrombin and thrombin are present in brain using specific monoclonal and polyclonal antibodies for both proteins. All antibodies stained residual serum in blood vessels, as well as normal pyramidal neurons and their processes, and some astrocytes. Additionally, in AD and PDCG cases, all antibodies stained extra- and intracellular neurofibrillary tangles (NFTs), senile plaques, and reactive microglial cells. The ubiquitous expression of prothrombin and thrombin in brain cells suggests that thrombin plays an important physiological role in normal brain. The accumulation of thrombin and prothrombin in NFTs supports the hypothesis that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases.
    Journal of Neuropathology and Experimental Neurology 02/2006; 65(1):19-25. · 4.35 Impact Factor
  • Article: P3-335
    Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2006; 2(3).
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    ABSTRACT: The microtubule-associated protein tau aggregates intracellularly by unknown mechanisms in Alzheimer's disease and other tauopathies. A contributing factor may be a failure to break down free cytosolic tau, thus creating a surplus for aggregation, although the proteases that degrade tau in brain remain unknown. To address this issue, we prepared cytosolic fractions from five normal human brains and from perfused rat brains and incubated them with or without protease inhibitors. D-Phenylalanyl-L-prolylarginyl chloromethyl ketone, a thrombin-specific inhibitor, prevented tau breakdown in these fractions, suggesting that thrombin is a brain protease that processes tau. We next exposed human recombinant tau to purified human thrombin and analyzed the fragments by N-terminal sequencing. We found that thrombin proteolyzed tau at multiple arginine and lysine sites. These include Arg(155)-Gly(156), Arg(209)-Ser(210), Arg(230)-Thr(231), Lys(257)-Ser(258), and Lys(340)-Ser(341) (numbering according to the longest human tau isoform). Temporally, the initial cleavage occurred at the Arg(155)-Gly(156) bond. Proteolysis of the resultant C-terminal tau fragment then proceeded bidirectionally. When tau was phosphorylated by glycogen synthase kinase-3beta, most of these proteolytic processes were inhibited, except for the first cleavage at the Arg(155)-Gly(156) bond. Furthermore, paired helical filament tau prepared from Alzheimer's disease brain was more resistant to thrombin proteolysis than following dephosphorylation by alkaline phosphatase. The results suggest a possible role for thrombin in proteolysis of tau under physiological and/or pathological conditions in human brains. They are consistent with the hypothesis that phosphorylation of tau inhibits proteolysis by thrombin or other endogenous proteases, leading to aggregation of tau into insoluble fibrils.
    Journal of Biological Chemistry 03/2005; 280(7):5145-53. · 4.65 Impact Factor
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    ABSTRACT: We synthesized on cellulose membranes 4942 ten-amino-acid peptides which included all of the sequences predicted for the severe acute respiratory syndrome (SARS) corona virus. We probed these membranes with four pairs of acute and convalescent sera from recovered SARS cases. We correlated positively reacting peptides with the in vitro SARS-CoV neutralizing activity of the samples. We found that convalescent sera with high neutralizing activity recognized exclusively only a limited number of peptides on the membranes. This suggests that antibodies against the epitopes represented by these peptides could be responsible for much of the SARS-CoV neutralizing activity. The findings have implications for monitoring humoral responses to SARS-CoV as well as for developing a successful SARS vaccine.
    Virology 08/2004; 324(2):251-6. · 3.37 Impact Factor