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Tanzi, Rudolph

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Tanzi, Rudolph
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    Genetic Meta-Analysis of Diagnosed Alzheimer’s Disease Identifies New Risk Loci and Implicates Aβ, Tau, Immunity and Lipid Processing
    (Springer Science and Business Media LLC, 2019-02-28) Grenier-Boley, Benjamin; Sims, Rebecca; Bis, Joshua C.; Damotte, Vincent; Naj, Adam C.; Boland, Anne; Vronskaya, Maria; van der Lee, Sven J.; Amlie-Wolf, Alexandre; Bellenguez, Céline; Frizatti, Aura; Chouraki, Vincent; Martin, Eden R.; Sleegers, Kristel; Badarinarayan, Nandini; Jakobsdottir, Johanna; Hamilton-Nelson, Kara L.; Moreno-Grau, Sonia; Olaso, Robert; Raybould, Rachel; Chen, Yuning; Kuzma, Amanda B.; Hiltunen, Mikko; Morgan, Taniesha; Ahmad, Shahzad; Vardarajan, Badri N.; Epelbaum, Jacques; Hoffmann, Per; Boada, Merce; Beecham, Gary W.; Garnier, Jean-Guillaume; Harold, Denise; Fitzpatrick, Annette L.; Valladares, Otto; Moutet, Marie-Laure; Gerrish, Amy; Smith, Albert V.; Qu, Liming; Bacq, Delphine; Denning, Nicola; Jian, Xueqiu; Zhao, Yi; Del Zompo, Maria; Fox, Nick C.; Choi, Seung-Hoan; Mateo, Ignacio; Hughes, Joseph T.; Adams, Hieab H.; Malamon, John; Sanchez-Garcia, Florentino; Patel, Yogen; Brody, Jennifer A.; Dombroski, Beth A.; Naranjo, Maria Candida Deniz; Daniilidou, Makrina; Eiriksdottir, Gudny; Mukherjee, Shubhabrata; Wallon, David; Uphill, James; Aspelund, Thor; Cantwell, Laura B.; Garzia, Fabienne; Galimberti, Daniela; Hofer, Edith; Butkiewicz, Mariusz; Fin, Bertrand; Scarpini, Elio; Sarnowski, Chloe; Bush, Will S.; Meslage, Stéphane; Kornhuber, Johannes; White, Charles C.; Song, Yuenjoo; Barber, Robert C.; Engelborghs, Sebastiaan; Sordon, Sabrina; Voijnovic, Dina; Adams, Perrie M.; Vandenberghe, Rik; Mayhaus, Manuel; Cupples, L. Adrienne; Albert, Marilyn S.; De Deyn, Peter P.; Gu, Wei; Himali, Jayanadra J.; Beekly, Duane; Squassina, Alessio; Hartmann, Annette M.; Orellana, Adelina; Blacker, Deborah; Rodriguez-Rodriguez, Eloy; Lovestone, Simon; Garcia, Melissa E.; Doody, Rachelle S.; Munoz-Fernadez, Carmen; Sussams, Rebecca; Lin, Honghuang; Fairchild, Thomas J.; Benito, Yolanda A.; Holmes, Clive; Karamujić-Čomić, Hata; Frosch, Matthew P.; Thonberg, Hakan; Maier, Wolfgang; Roshchupkin, Gennady; Ghetti, Bernardino; Giedraitis, Vilmantas; Kawalia, Amit; Li, Shuo; Huebinger, Ryan M.; Kilander, Lena; Moebus, Susanne; Hernández, Isabel; Kamboh, M. Ilyas; Brundin, RoseMarie; Turton, James; Yang, Qiong; Katz, Mindy J.; Concari, Letizia; Lord, Jenny; Beiser, Alexa S.; Keene, C. Dirk; Helisalmi, Seppo; Kloszewska, Iwona; Kukull, Walter A.; Koivisto, Anne Maria; Lynch, Aoibhinn; Tarraga, Lluís; Larson, Eric B.; Haapasalo, Annakaisa; Lawlor, Brian; Mosley, Thomas H.; Lipton, Richard B.; Solfrizzi, Vincenzo; Gill, Michael; Longstreth, W. T.; Montine, Thomas J.; Frisardi, Vincenza; Diez-Fairen, Monica; Rivadeneira, Fernando; Petersen, Ronald C.; Deramecourt, Vincent; Alvarez, Ignacio; Salani, Francesca; Ciaramella, Antonio; Boerwinkle, Eric; Reiman, Eric M.; Fievet, Nathalie; Rotter, Jerome I.; Reisch, Joan S.; Hanon, Olivier; Cupidi, Chiara; Andre Uitterlinden, A. G.; Royall, Donald R.; Dufouil, Carole; Maletta, Raffaele Giovanni; de Rojas, Itziar; Sano, Mary; Brice, Alexis; Cecchetti, Roberta; George-Hyslop, Peter St; Ritchie, Karen; Tsolaki, Magda; Tsuang, Debby W.; Dubois, Bruno; Craig, David; Wu, Chuang-Kuo; Soininen, Hilkka; Avramidou, Despoina; Albin, Roger L.; Fratiglioni, Laura; Germanou, Antonia; Apostolova, Liana G.; Keller, Lina; Koutroumani, Maria; Arnold, Steven E.; Panza, Francesco; Gkatzima, Olymbia; Asthana, Sanjay; Hannequin, Didier; Whitehead, Patrice; Atwood, Craig S.; Caffarra, Paolo; Hampel, Harald; Quintela, Inés; Carracedo, Ángel; Lannfelt, Lars; Rubinsztein, David C.; Barnes, Lisa L.; Pasquier, Florence; Frölich, Lutz; Barral, Sandra; McGuinness, Bernadette; Beach, Thomas G.; Johnston, Janet A.; Becker, James T.; Passmore, Peter; Bigio, Eileen H.; Schott, Jonathan M.; Bird, Thomas D.; Warren, Jason D.; Boeve, Bradley F.; Lupton, Michelle K.; Bowen, James D.; Proitsi, Petra; Boxer, Adam; Powell, John F.; Burke, James R.; Kauwe, John S. K.; Burns, Jeffrey M.; Mancuso, Michelangelo; Buxbaum, Joseph D.; Bonuccelli, Ubaldo; Cairns, Nigel J.; McQuillin, Andrew; Cao, Chuanhai; Livingston, Gill; Carlson, Chris S.; Bass, Nicholas J.; Carlsson, Cynthia M.; Hardy, John; Carney, Regina M.; Bras, Jose; Carrasquillo, Minerva M.; Guerreiro, Rita; Allen, Mariet; Chui, Helena C.; Fisher, Elizabeth; Masullo, Carlo; Crocco, Elizabeth A.; DeCarli, Charles; Bisceglio, Gina; Dick, Malcolm; Ma, Li; Duara, Ranjan; Graff-Radford, Neill R.; Evans, Denis A.; Hodges, Angela; Faber, Kelley M.; Scherer, Martin; Fallon, Kenneth B.; Riemenschneider, Matthias; Fardo, David W.; Heun, Reinhard; Farlow, Martin R.; Kölsch, Heike; Ferris, Steven; Leber, Markus; Foroud, Tatiana M.; Heuser, Isabella; Galasko, Douglas R.; Giegling, Ina; Gearing, Marla; Hüll, Michael; Geschwind, Daniel H.; Gilbert, John R.; Morris, John; Mayo, Kevin; Feulner, Thomas; Hamilton, Ronald L.; Harrell, Lindy E.; Drichel, Dmitriy; Honig, Lawrence S.; Cushion, Thomas D.; Huentelman, Matthew J.; Hollingworth, Paul; Hulette, Christine M.; Marshall, Rachel; Jarvik, Gail P.; Meggy, Alun; Abner, Erin; Menzies, Georgina E.; Jin, Lee-Way; Leonenko, Ganna; Real, Luis M.; Jun, Gyungah R.; Baldwin, Clinton T.; Grozeva, Detelina; Karydas, Anna; Russo, Giancarlo; Kaye, Jeffrey A.; Kim, Ronald; Jessen, Frank; Kowall, Neil W.; Vellas, Bruno; Kramer, Joel H.; Vardy, Emma; LaFerla, Frank M.; Jöckel, Karl-Heinz; Lah, James J.; Dichgans, Martin; Leverenz, James B.; Mann, David; Levey, Allan I.; Pickering-Brown, Stuart; Lieberman, Andrew P.; Klopp, Norman; Lunetta, Kathryn L.; Wichmann, H-Erich; Lyketsos, Constantine G.; Morgan, Kevin; Marson, Daniel C.; Brown, Kristelle; Martiniuk, Frank; Medway, Christopher; Mash, Deborah C.; Nöthen, Markus M.; Masliah, Eliezer; Hooper, Nigel M.; McCormick, Wayne C.; Daniele, Antonio; McCurry, Susan M.; Bayer, Anthony; McDavid, Andrew N.; Gallacher, John; McKee, Ann C.; van den Bussche, Hendrik; Mesulam, Marsel; Brayne, Carol; Miller, Bruce L.; Riedel-Heller, Steffi; Miller, Carol A.; Miller, Joshua W.; Al-Chalabi, Ammar; Morris, John C.; Shaw, Christopher E.; Myers, Amanda J.; Wiltfang, Jens; O’Bryant, Sid; Olichney, John M.; Alvarez, Victoria; Parisi, Joseph E.; Singleton, Andrew B.; Paulson, Henry L.; Collinge, John; Perry, William R.; Mead, Simon; Peskind, Elaine; Cribbs, David H.; Rossor, Martin; Pierce, Aimee; Ryan, Natalie S.; Poon, Wayne W.; Nacmias, Benedetta; Potter, Huntington; Sorbi, Sandro; Quinn, Joseph F.; Sacchinelli, Eleonora; Raj, Ashok; Spalletta, Gianfranco; Raskind, Murray; Caltagirone, Carlo; Bossù, Paola; Orfei, Maria Donata; Reisberg, Barry; Clarke, Robert; Reitz, Christiane; Smith, A David; Ringman, John M.; Warden, Donald; Roberson, Erik D.; Wilcock, Gordon; Rogaeva, Ekaterina; Bruni, Amalia Cecilia; Rosen, Howard J.; Gallo, Maura; Rosenberg, Roger N.; Ben-Shlomo, Yoav; Sager, Mark A.; Mecocci, Patrizia; Saykin, Andrew J.; Pastor, Pau; Cuccaro, Michael L.; Vance, Jeffery M.; Schneider, Julie A.; Schneider, Lori S.; Slifer, Susan; Seeley, William W.; Smith, Amanda G.; Sonnen, Joshua A.; Spina, Salvatore; Stern, Robert A.; Swerdlow, Russell H.; Tang, Mitchell; Trojanowski, John Q.; Troncoso, Juan C.; Van Deerlin, Vivianna M.; Van Eldik, Linda J.; Vinters, Harry V.; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Wilhelmsen, Kirk C.; Williamson, Jennifer; Wingo, Thomas S.; Woltjer, Randall L.; Wright, Clinton B.; Yu, Chang-En; Yu, Lei; Saba, Yasaman; Pilotto, Alberto; Bullido, Maria J.; Peters, Oliver; Crane, Paul K.; Bennett, David; Bosco, Paola; Coto, Eliecer; Boccardi, Virginia; De Jager, Phil L.; Lleo, Alberto; Warner, Nick; Lopez, Oscar L.; Ingelsson, Martin; Deloukas, Panagiotis; Cruchaga, Carlos; Graff, Caroline; Gwilliam, Rhian; Fornage, Myriam; Goate, Alison M.; Sanchez-Juan, Pascual; Kehoe, Patrick G.; Amin, Najaf; Ertekin-Taner, Nilifur; Berr, Claudine; Debette, Stéphanie; Love, Seth; Launer, Lenore J.; Younkin, Steven G.; Dartigues, Jean-Francois; Corcoran, Chris; Ikram, M. Arfan; Dickson, Dennis W.; Nicolas, Gael; Campion, Dominique; Tschanz, JoAnn; Schmidt, Helena; Hakonarson, Hakon; Clarimon, Jordi; Munger, Ron; Schmidt, Reinhold; Farrer, Lindsay A.; Van Broeckhoven, Christine; C. O’Donovan, Michael; DeStefano, Anita L.; Jones, Lesley; Haines, Jonathan L.; Deleuze, Jean-Francois; Owen, Michael J.; Gudnason, Vilmundur; Mayeux, Richard; Escott-Price, Valentina; Psaty, Bruce M.; Ramirez, Alfredo; Wang, Li-San; Ruiz, Agustin; van Duijn, Cornelia M.; Holmans, Peter A.; Seshadri, Sudha; Williams, Julie; Amouyel, Phillippe; Schellenberg, Gerard D.; Lambert, Jean-Charles; Pericak-Vance, Margaret A.; Kunkle, Brian; Green, Robert; Growdon, John; Hyman, Bradley; Tanzi, Rudolph
    Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed the largest genome-wide association meta-analysis of clinically diagnosed LOAD to date (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1 and WWOX). Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins and APP metabolism, showing that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analysis of risk genes and pathways show enrichment for rare variants (P=1.32x10-7) indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.
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    Astrocytic interleukin-3 programs microglia and limits Alzheimer’s disease
    (Springer Science and Business Media LLC, 2021-07-14) McAlpine, Cameron; Park, Joseph; Griciuc, Ana; Kim, Eunhee; Choi, Se Hoon; Iwamoto, Yoshiko; Kiss, Máté G.; Christie, Kathleen; Vinegoni, Claudio; Poller, Wolfram; Mindur, John; Chan, Christopher; He, Shun; Janssen, Henrike; Wong, Lai Ping; Downey, Jeffrey; Singh, Sumnima; Anzai, Atsushi; Kahles, Florian; Jorfi, Mehdi; Feruglio, Paulo; Sadreyev, Ruslan; Weissleder, Ralph; Kleinstiver, Benjamin; Nahrendorf, Matthias; Tanzi, Rudolph; Swirski, Filip
    Communication within the glial cell ecosystem is essential to neuronal and brain health1–3. The influence of glial cells on β-amyloid (Aβ) and neurofibrillary tau accumulation and clearance in Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) reprograms microglia to ameliorate AD pathology. Upon recognition of Aβ deposits, microglia augment IL-3Rɑ, IL-3’s specific receptor, rendering them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional reprograming of microglia endowing them with an acute immune response program, enhanced motility, and the capacity to cluster and clear Aβ and tau aggregates. These changes restrict AD pathology and cognitive decline. This study identifies IL-3 as a critical mediator of astrocyte-microglia crosstalk and a node for therapeutic intervention in AD.
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    Adjusting heterogeneous ascertainment bias for genetic association analysis with extended families
    (BioMed Central, 2015) Park, Suyeon; Lee, Sungyoung; Lee, Young; Herold, Christine; Hooli, Basavaraj; Mullin, Kristina; Park, Taesung; Park, Changsoon; Bertram, Lars; Lange, Christoph; Tanzi, Rudolph; Won, Sungho
    Background: In family-based association analysis, each family is typically ascertained from a single proband, which renders the effects of ascertainment bias heterogeneous among family members. This is contrary to case–control studies, and may introduce sample or ascertainment bias. Statistical efficiency is affected by ascertainment bias, and careful adjustment can lead to substantial improvements in statistical power. However, genetic association analysis has often been conducted using family-based designs, without addressing the fact that each proband in a family has had a great influence on the probability for each family member to be affected. Method We propose a powerful and efficient statistic for genetic association analysis that considered the heterogeneity of ascertainment bias among family members, under the assumption that both prevalence and heritability of disease are available. With extensive simulation studies, we showed that the proposed method performed better than the existing methods, particularly for diseases with large heritability. Results: We applied the proposed method to the genome-wide association analysis of Alzheimer’s disease. Four significant associations with the proposed method were found. Conclusion: Our significant findings illustrated the practical importance of this new analysis method. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0198-6) contains supplementary material, which is available to authorized users.
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    Identification of clusters of rapid and slow decliners among subjects at risk for Alzheimer’s disease
    (Nature Publishing Group UK, 2017) Gamberger, Dragan; Lavrač, Nada; Srivatsa, Shantanu; Tanzi, Rudolph; Doraiswamy, P. Murali
    The heterogeneity of Alzheimer’s disease contributes to the high failure rate of prior clinical trials. We analyzed 5-year longitudinal outcomes and biomarker data from 562 subjects with mild cognitive impairment (MCI) from two national studies (ADNI) using a novel multilayer clustering algorithm. The algorithm identified homogenous clusters of MCI subjects with markedly different prognostic cognitive trajectories. A cluster of 240 rapid decliners had 2-fold greater atrophy and progressed to dementia at almost 5 times the rate of a cluster of 184 slow decliners. A classifier for identifying rapid decliners in one study showed high sensitivity and specificity in the second study. Characterizing subgroups of at risk subjects, with diverse prognostic outcomes, may provide novel mechanistic insights and facilitate clinical trials of drugs to delay the onset of AD.
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    Cromolyn Reduces Levels of the Alzheimer’s Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis
    (Nature Publishing Group UK, 2018) Zhang, Can; Griciuc, Ana; Hudry, Eloise; Wan, Yu; Quinti, Luisa; Ward, Joseph; Forte, Angela M.; Shen, Xunuo; Ran, Chongzhao; Elmaleh, David; Tanzi, Rudolph
    Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer’s disease (AD). Aβ deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aβ levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APPSwedish-expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of β-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aβ species, i.e. Aβ40 and Aβ42, but increased insoluble Aβ38 levels. In addition to its anti-aggregation effects on Aβ, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of β-amyloid deposits in AD mice. Cromolyn also promoted Aβ42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aβ levels and inducing a neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.
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    The Pathway Coexpression Network: Revealing pathway relationships
    (Public Library of Science, 2018) Pita-Juárez, Yered; Altschuler, Gabriel; Kariotis, Sokratis; Wei, Wenbin; Koler, Katjuša; Green, Claire; Tanzi, Rudolph; Hide, Winston
    A goal of genomics is to understand the relationships between biological processes. Pathways contribute to functional interplay within biological processes through complex but poorly understood interactions. However, limited functional references for global pathway relationships exist. Pathways from databases such as KEGG and Reactome provide discrete annotations of biological processes. Their relationships are currently either inferred from gene set enrichment within specific experiments, or by simple overlap, linking pathway annotations that have genes in common. Here, we provide a unifying interpretation of functional interaction between pathways by systematically quantifying coexpression between 1,330 canonical pathways from the Molecular Signatures Database (MSigDB) to establish the Pathway Coexpression Network (PCxN). We estimated the correlation between canonical pathways valid in a broad context using a curated collection of 3,207 microarrays from 72 normal human tissues. PCxN accounts for shared genes between annotations to estimate significant correlations between pathways with related functions rather than with similar annotations. We demonstrate that PCxN provides novel insight into mechanisms of complex diseases using an Alzheimer’s Disease (AD) case study. PCxN retrieved pathways significantly correlated with an expert curated AD gene list. These pathways have known associations with AD and were significantly enriched for genes independently associated with AD. As a further step, we show how PCxN complements the results of gene set enrichment methods by revealing relationships between enriched pathways, and by identifying additional highly correlated pathways. PCxN revealed that correlated pathways from an AD expression profiling study include functional clusters involved in cell adhesion and oxidative stress. PCxN provides expanded connections to pathways from the extracellular matrix. PCxN provides a powerful new framework for interrogation of global pathway relationships. Comprehensive exploration of PCxN can be performed at http://pcxn.org/.
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    Human Neurospheroid Arrays for In Vitro Studies of Alzheimer’s Disease
    (Nature Publishing Group UK, 2018) Jorfi, Mehdi; D’Avanzo, Carla; Tanzi, Rudolph; Kim, Doo Yeon; Irimia, Daniel
    Neurospheroids are commonly used for in vitro disease modeling and drug screening. However, the heterogeneity in size of the neurospheroids mixtures available through current methods limits their utility when employed for basic mechanistic studies of neurodegenerative diseases or screening for new interventions. Here, we generate neurospheroids from immortalized neural progenitor cells and human induced pluripotent stem cells that are uniform in size, into large-scale arrays. In proof of concept experiments, we validate the neurospheroids array as a sensitive and robust tool for screening compounds over extended time. We show that when suspended in three-dimensional extracellular matrix up to several weeks, the stem cell-derived neurospheroids display extensive neurite outgrowth and extend thick bundles of dendrites outward. We also cultivate genetically-engineered stem cell-derived neurospheroids with familial Alzheimer’s disease mutations for eight weeks in our microarray system. Interestingly, we observed robust accumulation of amyloid-β and phosphorylated tau, key hallmarks of Alzheimer’s disease. Overall, our in vitro model for engineering neurospheroid arrays is a valuable tool for studying complex neurodegenerative diseases and accelerating drug discovery.
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    Sex Differences in Cognitive Decline in Subjects with High Likelihood of Mild Cognitive Impairment due to Alzheimer’s disease
    (Nature Publishing Group UK, 2018) Sohn, Dongwha; Shpanskaya, Katie; Lucas, Joseph E.; Petrella, Jeffrey R.; Saykin, Andrew J.; Tanzi, Rudolph; Samatova, Nagiza F.; Doraiswamy, P. Murali
    Sex differences in Alzheimer’s disease (AD) biology and progression are not yet fully characterized. The goal of this study is to examine the effect of sex on cognitive progression in subjects with high likelihood of mild cognitive impairment (MCI) due to Alzheimer’s and followed up to 10 years in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Cerebrospinal fluid total-tau and amyloid-beta (Aβ42) ratio values were used to sub-classify 559 MCI subjects (216 females, 343 males) as having “high” or “low” likelihood for MCI due to Alzheimer’s. Data were analyzed using mixed-effects models incorporating all follow-ups. The worsening from baseline in Alzheimer’s Disease Assessment Scale-Cognitive score (mean, SD) (9 ± 12) in subjects with high likelihood of MCI due to Alzheimer’s was markedly greater than that in subjects with low likelihood (1 ± 6, p < 0.0001). Among MCI due to AD subjects, the mean worsening in cognitive score was significantly greater in females (11.58 ± 14) than in males (6.87 ± 11, p = 0.006). Our findings highlight the need to further investigate these findings in other populations and develop sex specific timelines for Alzheimer’s disease progression.
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    The double-edged role of copper in the fate of amyloid beta in the presence of anti-oxidants† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c7sc01787a Click here for additional data file.
    (Royal Society of Chemistry, 2017) Yang, Jing; Zhang, Xueli; Zhu, Yiying; Lenczowski, Emily; Tian, Yanli; Yang, Jian; Zhang, Can; Hardt, Markus; Qiao, Chunhua; Tanzi, Rudolph; Moore, Anna; Ye, Hui; Ran, Chongzhao
    The biological fate of amyloid beta (Aβ) species is a fundamental question in Alzheimer’s disease (AD) pathogenesis. The competition between clearance and aggregation of Aβs is critical for the onset of AD. Copper has been widely considered to be an inducer of harmful crosslinking of Aβs, and an important triggering factor for the onset of AD. In this report, however, we present data to show that copper can also be an inducer of Aβ degradation in the presence of a large excess of well-known intrinsic (such as dopamine) or extrinsic (such as vitamin C) anti-oxidants. The degraded fragments were identified using SDS-Page gels, and validated via nanoLC-MS/MS. A tentative mechanism for the degradation was proposed and validated with model peptides. In addition, we performed electrophysiological analysis to investigate the synaptic functions in brain slices, and found that in the presence of a significant excess of vitamin C, Cu(ii) could prevent an Aβ-induced deficit in synaptic transmission in the hippocampus. Collectively, our evidence strongly indicated that a proper combination of copper and anti-oxidants might have a positive effect on the prevention of AD. This double-edged function of copper in AD has been largely overlooked in the past. We believe that our report is very important for fully understanding the function of copper in AD pathology.
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    Soluble Gamma-secretase Modulators Attenuate Alzheimer's β-amyloid Pathology and Induce Conformational Changes in Presenilin 1
    (Elsevier, 2017) Raven, Frank; Ward, Joseph F.; Zoltowska, Katarzyna; Wan, Yu; Bylykbashi, Enjana; Miller, Sean J.; Shen, Xunuo; Choi, Se Hoon; Rynearson, Kevin D.; Berezovska, Oksana; Wagner, Steven L.; Tanzi, Rudolph; Zhang, Can
    A central pathogenic event of Alzheimer's disease (AD) is the accumulation of the Aβ42 peptide, which is generated from amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. We have developed a class of soluble 2-aminothiazole γ-secretase modulators (SGSMs) that preferentially decreases Aβ42 levels. However, the effects of SGSMs in AD animals and cells expressing familial AD mutations, as well as the mechanism of γ-secretase modulation remain largely unknown. Here, a representative of this SGSM scaffold, SGSM-36, was investigated using animals and cells expressing FAD mutations. SGSM-36 preferentially reduced Aβ42 levels without affecting either α- and β-secretase processing of APP nor Notch processing. Furthermore, an allosteric site was identified within the γ-secretase complex that allowed access of SGSM-36 using cell-based, fluorescence lifetime imaging microscopy analysis. Collectively, these studies provide mechanistic insights regarding SGSMs of this class and reinforce their therapeutic potential in AD.