[en] The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer's disease.
Disciplines :
Neurology
Author, co-author :
Venegas, Carmen; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Kumar, Sathish; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Franklin, Bernardo S; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Dierkes, Tobias; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany ; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Brinkschulte, Rebecca; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Tejera, Dario; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Vieira-Saecker, Ana; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Schwartz, Stephanie; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Santarelli, Francesco; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Kummer, Markus P; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Griep, Angelika; Department of Neurodegenerative Diseases and Gerontopsychiatry, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany
Gelpi, Ellen; Neurological Tissue Bank, University of Barcelona-Hospital Clinic, IDIBAPS, 08036 Barcelona, Spain
Beilharz, Michael; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Riedel, Dietmar; Electron Microscopy Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
Golenbock, Douglas T; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA
Geyer, Matthias; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany
Walter, Jochen; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Latz, Eicke; Institute of Innate Immunity, University of Bonn, 53127 Bonn, Germany ; Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA ; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
HENEKA, Michael ; University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany > Department of Neurodegenerative Diseases and Gerontopsychiatry ; University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA > Department of Infectious Diseases and Immunology ; Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, Germany
Acknowledgements This work was funded by the Deutsche Forschungs-gemeinschaft through the Cluster of Excellence “Immunosensation” (to M.T.H., E.L., M.G. and B.S.F.), the Clinical Research Group (KFO177; to M.T.H., E.L. and J.W.), the SFB670 (E.L.), grant WA1477/6 (J.W.), ERC InflammAct (E.L.), ERC PLAT-IL-1 (B.S.F.), the ERA-NET consortium TracInflam (M.T.H.) and JPND consortium InCure (M.T.H.).
Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463-477 (2014).
Lambert, J. C. et al. Meta-analysis of 74, 046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45, 1452-1458 (2013).
Yokoyama, J. S. et al. Association between genetic traits for immunemediated diseases and Alzheimer disease. JAMA Neurol. 73, 691-697 (2016).
Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer's disease. Nature 518, 365-369 (2015).
Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153, 707-720 (2013).
Raj, T. et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science 344, 519-523 (2014).
Karch, C. M., Cruchaga, C. & Goate, A. M. Alzheimer's disease genetics: from the bench to the clinic. Neuron 83, 11-26 (2014).
Musiek, E. S. & Holtzman, D. M. Three dimensions of the amyloid hypothesis: time, space and 'wingmen'. Nat. Neurosci. 18, 800-806 (2015).
Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45-51 (2013).
Jack, C. R. Jr et al. Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207-216 (2013).
Heneka, M. T., Golenbock, D. T. & Latz, E. Innate immunity in Alzheimer's disease. Nat. Immunol. 16, 229-236 (2015).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674-678 (2013).
Lu, A. et al. Unified polymerization mechanism for the assembly of ASCdependent inflammasomes. Cell 156, 1193-1206 (2014).
Masumoto, J. et al. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J. Biol. Chem. 274, 33835-33838 (1999).
Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 1207-1222 (2014).
Franklin, B. S. et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat. Immunol. 15, 727-737 (2014).
Baroja-Mazo, A. et al. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15, 738-748 (2014).
Dick, M. S., Sborgi, L., Rühl, S., Hiller, S. & Broz, P. ASC filament formation serves as a signal amplification mechanism for inflammasomes. Nat. Commun. 7, 11929 (2016).
Tomiyama, T. et al. A new amyloid β variant favoring oligomerization in Alzheimer's-type dementia. Ann. Neurol. 63, 377-387 (2008).
Borchelt, D. R. et al. Familial Alzheimer's disease-linked presenilin 1 variants elevate Aβ 1-42/1-40 ratio in vitro and in vivo. Neuron 17, 1005-1013 (1996).
Scheuner, D. et al. Secreted amyloid β -protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat. Med. 2, 864-870 (1996).
Youm, Y.-H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519-532 (2013).
Meyer-Luehmann, M. et al. Exogenous induction of cerebral β -amyloidogenesis is governed by agent and host. Science 313, 1781-1784 (2006).
Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745-757 (2011).
Nuvolone, M., Sorce, S., Schwarz, P. & Aguzzi, A. Prion pathogenesis in the absence of NLRP3/ASC inflammasomes. PLoS ONE 10, e0117208 (2015)
Yamanaka, M. et al. PPARγ /RXRα -induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J. Neurosci. 32, 17321-17331 (2012).
Fernandes-Alnemri, T. & Alnemri, E. S. Assembly, purification, and assay of the activity of the ASC pyroptosome. Methods Enzymol. 442, 251-270 (2008).
Fernandes-Alnemri, T. et al. The pyroptosome: a supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation. Cell Death Differ. 14, 1590-1604 (2007).
Wahle, T. et al. GGA1 is expressed in the human brain and affects the generation of amyloid β -peptide. J. Neurosci. 26, 12838-12846 (2006).
Kumar, S. et al. Extracellular phosphorylation of the amyloid β -peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J. 30, 2255-2265 (2011).
Rostagno, A. & Ghiso, J. Isolation and biochemical characterization of amyloid plaques and paired helical filaments. Curr. Protoc. Cell. Biol. 44, 3.33.1-3.33.33 (2009).
Fritschi, S. K. et al. Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol. 128, 477-484 (2014).
Jäger, S. et al. α -secretase mediated conversion of the amyloid precursor protein derived membrane stub C99 to C83 limits Aβ generation. J. Neurochem. 111, 1369-1382 (2009).
