Person: Moir, Robert
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Moir
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Moir, Robert
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Publication Peroxidase Activity of Cyclooxygenase-2 (COX-2) Cross-links []-Amyloid (A[]) and Generates A[]-COX-2 Hetero-oligomers That Are Increased in Alzheimer's Disease(American Society for Biochemistry & Molecular Biology (ASBMB), 2004-01-14) Nagano, Seiichi; Huang, Xudong; Payton, Sandra M.; Tanzi, Rudolph E.; Bush, Ashley I.; Moir, RobertOxidative stress is associated with the neuropathology of Alzheimer's disease. We have previously shown that human Abeta has the ability to reduce Fe(III) and Cu(II) and produce hydrogen peroxide coupled with these metals, which is correlated with toxicity against primary neuronal cells. Cyclooxygenase (COX)-2 expression is linked to the progression and severity of pathology in AD. COX is a heme-containing enzyme that produces prostaglandins, and the enzyme also possesses peroxidase activity. Here we investigated the possibility of direct interaction between human Abeta and COX-2 being mediated by the peroxidase activity. Human Abeta formed dimers when it was reacted with COX-2 and hydrogen peroxide. Moreover, the peptide formed a cross-linked complex directly with COX-2. Such cross-linking was not observed with rat Abeta, and the sole tyrosine residue specific for human Abeta might therefore be the site of cross-linking. Similar complexes of Abeta and COX-2 were detected in post-mortem brain samples in greater amounts in AD tissue than in age-matched controls. COX-2-mediated cross-linking may inhibit Abeta catabolism and possibly generate toxic intracellular forms of oligomeric Abeta.Publication Isoflurane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia(Oxford University Press (OUP), 2006) Xie, Zhongcong; Dong, Y.; Maeda, U.; Moir, Robert; Inouye, Sharon; Culley, Deborah; Crosby, Gregory; Tanzi, RudolphBackground. Dementia and delirium have been postulated to share common pathophysiologic mechanisms; however, identification of these unifying mechanisms has remained elusive. The inhalation anesthetic isoflurane has been shown to enhance β-amyloid protein (Aβ) oligomerization and generation, to potentiate the cytotoxicity of Aβ, and to induce apoptosis. To address the molecular mechanisms of dementia and delirium associated with anesthesia and surgery, we assessed whether the Aβ fibrillar aggregation inhibitor Congo red can attenuate isoflurane-induced caspase-3 activation in H4 human neuroglioma cells overexpressing human β-amyloid precursor protein (APP). Methods. H4 human neuroglioma cells stably transfected to express human full-length wild-type APP were exposed to 2% isoflurane for 6 hours. The cells were harvested at the end of the treatment. Caspase-3 activation was measured with quantitative Western blotting. Results. We found that isoflurane induces cellular apoptosis in a dose-dependent manner, and that Congo red inhibits isoflurane-induced apoptosis in H4 human neuroglioma cells overexpressing APP. Interestingly, Congo red also inhibits staurosporine-induced apoptosis. Conclusion. The demonstration that isoflurane contributes to well-described mechanisms of Alzheimer's neuropathogenesis provides a plausible link between the acute effects of anesthesia, a well-described risk factor for delirium, and the more long-term sequelae of dementia. These findings suggest that isoflurane-induced Aβ oligomerization and apoptosis may contribute to the risk of postoperative cognitive dysfunction and provide a potential pathogenic link between delirium and dementia.Publication Amyloid-β Protein Protects Against Microbial Infection In Transgenic C. elegans and 5XFAD Mice(American Association for the Advancement of Science (AAAS), 2016) Kumar, Deepak; Choi, Se Hoon; Washicosky, Kevin J.; Eimer, William; Tucker, Stephanie Catherine; Ghofrani, Jessica; Lefkowitz, Aaron; McColl, Gawain; Goldstein, Lee E.; Tanzi, Rudolph; Moir, RobertThe amyloid-β peptide (Aβ) is a key protein in Alzheimer's disease (AD) pathology. We previously reported in vitro evidence suggesting Aβ is an antimicrobial peptide. Here we provide the first in vivo evidence showing high Aβ production protects against fungal and bacterial infections in mouse and nematode AD models. In Aβ-null mouse models low Aβ production is associated with attenuated resistance to infection. Regarding mechanism, we show Aβ oligomerization, a behavior traditionally viewed as intrinsically pathological, is necessary for the antimicrobial activities of the peptide. Soluble Aβ oligomers bind microbial cell walls, developing protofibrils inhibit pathogen host cell adhesion, and, finally, proteaseresistant β-amyloid fibrils agglutinate and entrap the invading microbes. We also show that infection of 5XFAD mouse brain with S. Typhimurium bacteria rapidly seeds and dramatically accelerates β-amyloid deposition, which closely co-localizes with invading bacteria. Collectively, our findings raise the intriguing possibility that β-amyloid plays a protective role in innate immunity and infectious or sterile inflammatory stimuli may drive amyloidosis. These data suggest a dual protective/damaging role for Aβ, as has been described for other antimicrobial peptides.Publication Alzheimer's Disease Amyloid-\(\beta\) Links Lens and Brain Pathology in Down Syndrome(Public Library of Science, 2010) Moncaster, Juliet A.; Lu, Suqian; Burton, Mark A.; Ghosh, Joy G.; Soscia, Stephanie J.; Mocofanescu, Anca; Kuszak, Jer R.; Pineda, Roberto; Moir, Robert; Ericsson, Maria; Folkerth, Rebecca D.; Robb, Richard; Clark, John I.; Tanzi, Rudolph; Hunter, David; Goldstein, LeeDown syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-\(\beta\) peptides (A\(\beta\)), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased A\(\beta\) accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked A\(\beta\) pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear A\(\beta\) accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic A\(\beta\) aggregates (\(\sim\)5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of A\(\beta\) in DS lenses. Incubation of synthetic A\(\beta\) with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased A\(\beta\) accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.Publication The Alzheimer's Disease-Associated Amyloid \(\beta\)-Protein Is an Antimicrobial Peptide(Public Library of Science, 2010) Soscia, Stephanie; Kirby, James; Washicosky, Kevin J.; Tucker, Stephanie; Ingelsson, Martin; Hyman, Bradley; Burton, Mark A.; Duong, Scott; Tanzi, Rudolph; Moir, Robert; Goldstein, Lee E.Background: The amyloid \(\beta\)-protein (A\(\beta\)) is believed to be the key mediator of Alzheimer's disease (AD) pathology. A\(\beta\) is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, A\(\beta\) has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings: Here, we provide data supporting an in vivo function for A\(\beta\) as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of A\(\beta\) and LL-37, an archetypical human AMP. Findings reveal that A\(\beta\) exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue A\(\beta\) levels. Consistent with A\(\beta\)-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-A\(\beta\) antibodies. Conclusions/Significance: Our findings suggest A\(\beta\) is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of A\(\beta\)-mediated pathology and has important implications for ongoing and future AD treatment strategies.Publication The Alzheimer’s Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide(Public Library of Science, 2010) Kirby, James; Washicosky, Kevin J.; Tucker, Stephanie M.; Ingelsson, Martin; Hyman, Bradley; Burton, Mark A.; Goldstein, Lee E.; Duong, Scott; Tanzi, Rudolph; Moir, RobertBackground: The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings: Here, we provide data supporting an in vivo function for Aβ as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Aβ and LL-37, an archetypical human AMP. Findings reveal that Aβ exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. Conclusions/Significance: Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies.Publication Characterization of a Drosophila Alzheimer's Disease Model: Pharmacological Rescue of Cognitive Defects(Public Library of Science, 2011) Chakraborty, Ranjita; Vepuri, Vidya; Mhatre, Siddhita D.; Paddock, Brie E.; Miller, Sean; Michelson, Sarah J.; Delvadia, Radha; Desai, Arkit; Vinokur, Marianna; Melicharek, David J.; Utreja, Suruchi; Khandelwal, Preeti; Ansaloni, Sara; Lee, Jeremy C.; Tabb, Loni P.; Saunders, Aleister J.; Marenda, Daniel R.; Goldstein, Lee E.; Moir, RobertTransgenic models of Alzheimer's disease (AD) have made significant contributions to our understanding of AD pathogenesis, and are useful tools in the development of potential therapeutics. The fruit fly, Drosophila melanogaster, provides a genetically tractable, powerful system to study the biochemical, genetic, environmental, and behavioral aspects of complex human diseases, including AD. In an effort to model AD, we over-expressed human APP and BACE genes in the Drosophila central nervous system. Biochemical, neuroanatomical, and behavioral analyses indicate that these flies exhibit aspects of clinical AD neuropathology and symptomology. These include the generation of A\(\beta_{40}\) and A\(\beta_{42}\), the presence of amyloid aggregates, dramatic neuroanatomical changes, defects in motor reflex behavior, and defects in memory. In addition, these flies exhibit external morphological abnormalities. Treatment with a \(\gamma\)-secretase inhibitor suppressed these phenotypes. Further, all of these phenotypes are present within the first few days of adult fly life. Taken together these data demonstrate that this transgenic AD model can serve as a powerful tool for the identification of AD therapeutic interventions.Publication Zinc-induced Alzheimer's Aβ1–40 Aggregation Is Mediated by Conformational Factors(American Society for Biochemistry & Molecular Biology (ASBMB), 1997-10-17) Atwood, Craig S.; Hartshorn, Mariana A.; Vonsattel, Jean-Paul; Huang, Xudong; Moir, Robert; Tanzi, Rudolph; Bush, AshleyThe heterogeneous precipitates of Aβ that accumulate in the brain cortex in Alzheimer's disease possess varying degrees of resistance to resolubilization. We previously found that Aβ1–40 is rapidly precipitated in vitro by physiological concentrations of zinc, a neurochemical that is highly abundant in brain compartments where Aβ is most likely to precipitate. We now present evidence that the zinc-induced precipitation of Aβ is mediated by a peptide dimer and favored by conditions that promote α-helical and diminish β-sheet conformations. The manner in which the synthetic peptide is solubilized was critical to its behaviorin vitro. Zinc-induced Aβ aggregation was dependent upon the presence of NaCl, was enhanced by α-helical-promoting solvents, but was abolished when the peptide stock solution was stored frozen. The Aβ aggregates induced by zinc were reversible by chelation, but could then be reprecipitated by zinc for several cycles, indicating that the peptide's conformation is probably preserved in the zinc-mediated assembly. In contrast, Aβ aggregates induced by low pH (5.5) were not resolubilized by returning the pH milieu to 7.4. The zinc-Aβ interaction exhibits features resembling the gelation process of zinc-mediated fibrin assembly, suggesting that, in events such as clot formation or injury, reversible Aβ assembly could be physiologically purposive. Such a mechanism is contemplated in the early evolution of diffuse plaques in Alzheimer's disease and suggests a possible therapeutic strategy for the resolubilization of some forms of Aβ deposit in the disease.