Abstract
Prions are the only convincingly demonstrated proteinaceous infectious particle, yet recent studies find that amyloid-β peptide (Aβ) aggregates are capable of self-propagation, which induces amyloidosis pathology in Alzheimer’s disease (AD) model mice that is similar to the self-propagation phenomenon of prions in neurons. Gliosis is a common hallmark of AD and prion diseases, in which activated microglia accumulate around abnormal protein deposits. Analyses of the characteristics of activated microglia induced by Aβ in comparison with those induced by prions will provide new insight into the pathogenesis of AD. Therefore, we compared the characteristics of BV-2 cells (model microglia) activated by Aβ fibrillar peptides (Aβ1-42) and prions (PrP106-126). Aβ1-42 and PrP106-126, as well as the supernatants of the media collected from BV-2 cells cocultured with Aβ1-42 and PrP106-126, were potent activators of BV-2 microglial activity, but the chemotaxis index (CI) induced by Aβ1-42 was significantly higher than that induced by PrP106-126 at each concentration. Aβ1-42 and PrP106-126 increased the proliferation index (PI) and upregulated monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor beta 1 (TGF-β1) expression after 12 h of exposure. Our results show that Aβ activates microglia and regulates microglial protein expression in a manner similar to prions and, thus, provide new insight into the pathogenesis of AD.
Similar content being viewed by others
References
Arispe N, Doh M (2002) Plasma membrane cholesterol controls the cytotoxicity of Alzheimer’s disease Aβ (1–40) and (1–42) peptides. FASEB J 16:1526–1536
Bamberger M, Harris ME, McDonald DR, Husemann J, Landreth GE (2003) A cell surface receptor complex for fibrillar-Amyloid mediates microglial activation. J Neurosci 23:2665–2674
Barnham KJ, Cappai R, Beyreuther K, Masters C, Hill AF (2006) Delineating common molecular mechanisms in Alzheimer’s and prion diseases. Trends Biochem Sci 31:465–472
Burdick D, Soreghan B, Kwon M, Kosmoski J, Knauer M, Henschen A et al (1992) Assembly and aggregation properties of synthetic Alzheimer’s A4/beta amyloid peptide analogs. J Biol Chem 267:546–554
Checler F, Vincent B (2002) Alzheimer’s and prion diseases: distinct pathologies, common proteolytic denominators. Trends Neurosci 25:616–620
Chromy BA, Nowak RJ, Lambert M (2003) Self-assembly of Aβ1-42 into globular neurotoxins. Biochemistry 42:12749–12760
Ciesielski-Treska J, Grant NJ, Ulrich G, Corrotte M, Bailly Y, Haeberle A-M et al (2004) Fibrillar prion peptide (106–126) and scrapie prion protein hamper phagocytosis in microglia. Glia 46:101–115
Dermaut B, Croes EA, Rademakers R, Van Den Broeck M, Cruts M et al (2003) PRNP Val 129 homozygosity increases risk for early-onset Alzheimer’s disease. Ann Neurol 3:409–412
El Khoury J, Toft M, Hickman SE et al (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432–438
Felton LM, Cunningham C, Rankine EL, Waters S, Boche D, Perry VH (2005) MCP-1 and murine prion disease: separation of early behavioural dysfunction from overt clinical disease. Neurobiol Dis 20:283–295
Forloni G, Angeretti N, Chiesa R, Monzani E, Salmona M, Bugiani O et al (1993) Neurotoxicity of a prion protein fragment. Nature 362:543–546
Franz M, Eiden M, Balkema-Buschmann A, Greenlee J, Schatzl H, Dunzendorfer S, Kaser A, Meierhofer C, Tilg H, Wiedermann CJ (2000) Dendritic cell migration in different micropore filter assays. Immunol Lett 71:5–11
Garção P, Oliveira CR, Agostinho P (2006) Comparative study of microglia activation induced by amyloid-beta and prion peptides: role in neurodegeneration. J Neurosci Res 84:182–193
Gavín R, Ureña J, Rangel A, Pastrana MA, Requena JR, Soriano E et al (2008) Fibrillar prion peptide PrP(106-126) treatment induces Dab1 phosphorylation and impairs APP processing and Aβ production in cortical neurons. Neurobiol Dis 30:243–254
Hainfellner JA, Wanschitz J, Jellinger K, Liberski PP, Gullotta F, Budka H (1998) Coexistence of Alzheimer-type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathol 96:116–122
Heneka MT (2006) Inflammation in Alzheimer’s disease. Clin Neurosci Res 6:247–260
Horvath RJ, Nutile-McMenemy N, Alkaitis MS, Deleo JA (2008) Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. J Neurochem 107:557–569
Ishizuka K, Kitamura T et al (1997) Identification of monocyte chemoattractant protein-1 in senile plaques and reactive microglia of Alzheimer’s disease. Psychiatry Clin Neurosci 51:135–138
Johnstone M, Gearing AJH, Miller KM (1993) A central role for astrocytes in the inflammatory response to β-amyloid; chemokines, cytokines and reactive oxygen species are produced. J Neuroimmunol 93:182–193
Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70(4):532–540
Jucker M, Walker LC (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501(7465):45–51
Kallithraka S, Bakker J, Clifford MN, Vallis L (2001) Correlations between saliva protein composition and some T-I parameters of astringency. Food Qual Prefer 12:145–152
Kaneider NC, Kaser A, Dunzendorfer S, Tilg H, Wiedermann CJ (2003) Sphingosine kinase-dependent migration of immature dendritic cells in response to neurotoxic prion protein fragment. J Virol 77:5535–5539
Konturek PC, Bazela K, Kukharskyy V, Bauer M, Hahn EG, Schuppan D (2005) Helicobacter pylori upregulates prion protein expression in gastric mucosa: a possible link to prion disease. World J Gastroenterol 11:7651–7656
Le Y, Yazawa H, Gong W, Yu Z, Ferrans VJ, Ferrans et al (2001) The neurotoxic prion peptide fragment PrP(106-126) is a chemotactic agonist for the G protein-coupled receptor formyl peptide receptor-like 1. J Immunol 166:1448–1451
Mathieu M, Chabry J (2004) Neurons and astrocytes respond to prion infection by inducing microglia recruitment. J Neurosci 24:620–627
Muhleisen H, Gehrmann J, Meyermann R (1995) Reactive microglia in Creutzfeldt–Jakob disease. Neuropathol Appl Neurobiol 6:505–517
Pike CJ, Walencewicz AJ, Glabe CJ, Cotman CW (1991) In vitro aging of β-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 563:311–314
Powers JM, Liu Y, Hair LS, Kascsack RJ, Lewis LD, Wester DD et al (1991) Concomitant Creutzfeldt-Jakob and Alzheimer diseases. Acta Neuropathol 83:95–98
Prat E, Baron P, Meda L, Scarpini E, Galimberti D, Ardolino G et al (2000) The human astrocytoma cell line U373MG produces monocyte chemotactic protein (MCP)-1 upon stimulation with β-amyloid protein. Neurosci Lett 283:177–180
Riemenschneider M, Klopp N, Xiang W, Wagenpfeil S, Vollmert C, Muller U et al (2004) Prion protein codon 129 polymorphism and risk of Alzheimer disease. Neurology 63(2):364–366
Roher AE, Ball MJ, Bhave SV, Wakade AR (1991) β-Amyloid from Alzheimer disease brains inhibits sprouting and survival of sympathetic neurons. Biochem Biophys Res Commun 174:572–579
Rota E, Bellone G, Rocca P, Bergamasco B, Emanuelli G, Ferrero P (2006) Increased intrathecal TGF-beta1, but not IL-12, IFN-gamma and IL-10 levels in Alzheimer’s disease patients. Neurol Sci 27:33–39
Safar J, Roller PP, Gajdusek DC, Gibbs CJ Jr (1993) Conformational transitions, dissociation, and unfolding of scrapie amyloid (prion) protein. J Biol Chem 268:20276–20284
Sasaki A, Yamaguchi H, Ogawa A, Sugihara S, Nakazato Y (1997) Microglia activation in early stages of amyloid beta protein deposition. Acta Neuropathol 94:316–322
Small DH, McLean CA (1999) Alzheimer’s disease and the amyloid β protein: what is the role of amyloid-β. J Neurochem 73:443–449
Stine WB, Dahlgren KN, Krafft GA, LaDu MJ (2003) In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem 278:11612–11622
Vascellari S, Orrù CD, Hughson AG, King D, Barron R, Wilham J et al (2012) Prion seeding activities of mouse scrapie strains with divergent PrPSc protease sensitivities and amyloid plaque content using RT-QuIC and eQuIC. PLoS One 7(11):e48969
Verma A, Prasad KN, Singh AK et al (2010) Evaluation of the MTT lymphocyte proliferation assay for the diagnosis of neurocysticercosis. J Microbiol Methods 81:175–178
Voigtländer T, Klöppel S, Birner P, Jarius C, Flicker H, Verghese-Nikolakaki S et al (2001) Marked increase of neuronal prion protein immunoreactivity in Alzheimer’s disease and human prion diseases. Acta Neuropathol 101:417–423
Vrotsos EG et al (2009) MCP-1 involvement in glial differentiation of neuroprogenitor cells through APP signaling. Brain Res Bull 79(2):97–103
Acknowledgments
This work was supported by the Natural Science Foundation of China (Project Nos. 81200994 and 31172293) and the Basic and Clinical Medical Research Project of Capital Medical University (Project No. 12JL01).
Author information
Authors and Affiliations
Corresponding authors
Additional information
Jian Tu and Baian Chen contributed equally to this work.
China Agricultural University and Capital Medical University are cofirst institutions in this work.
Rights and permissions
About this article
Cite this article
Tu, J., Chen, B., Yang, L. et al. Amyloid-β Activates Microglia and Regulates Protein Expression in a Manner Similar to Prions. J Mol Neurosci 56, 509–518 (2015). https://doi.org/10.1007/s12031-015-0553-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-015-0553-2