Genetic background modulates outcome of therapeutic amyloid peptides in treatment of neuroinflammation Allison Kraus a, ⁎, Brent Race a , Katie Phillips a , Clayton Winkler a , Greg Saturday b , Michael Kurnellas c , Jonathan B. Rothbard c,d , Bradley R. Groveman a , Lawrence Steinman c,d , Byron Caughey a a Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA b Rocky Mountain Veterinary Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA c Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA d Department of Medicine, Division of Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA abstract article info Article history: Received 15 April 2016 Received in revised form 27 May 2016 Accepted 22 June 2016 Available online xxxx Amyloid hexapeptide molecules are effective in the treatment of the murine model of neuroinflammation, known as experimental autoimmune encephalomyelitis (EAE). Efficacy however differs between two inbred mouse strains, C57BL/6J (B6) and C57BL/10SnJ (B10). Amyloid hexapeptide treatments improved the clinical outcomes of B6, but not B10 mice, indicating that genetic background influences therapeutic efficacy. Moreover, although previous studies indicated that prion protein deficiency results in more severe EAE in B6 mice, we ob- served no such effect in B10 mice. In addition, we found that amyloid hexapeptide treatments of B10 and B6 mice elicited differential IL4 responses. Thus, the modulatory potential of prion protein and related treatments with other amyloid hexapeptides in EAE depends on mouse strain. © 2016 Published by Elsevier B.V. Keywords: Experimental autoimmune encephalomyelitis Amyloid Prion protein 1. Introduction Amyloid formation is evident in the pathology of numerous diseases, including neurodegenerative diseases such as Alzheimer's and prion disease. Molecules with amyloid structure are, however, a part of nor- mal physiology. Functional amyloids occur naturally for storage of pep- tide hormones in the pituitary, for example (Maji et al., 2009). Emerging evidence suggests that endogenous expression of amyloid-forming pro- teins and exogenous administration of amyloid fibrils can reduce neuroinflammatory responses in autoimmune disease. Multiple lines of evidence demonstrate that amyloid fibrils can modulate autoimmune processes and decrease the severity of paralysis in the murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) (Grant et al., 2012; Kurnellas et al., 2013; Kurnellas et al., 2014). Further- more, targeted deletion of genes encoding proteins with the propensity to form amyloid results in more severe EAE disease in mice, implying a neuroprotective role for amyloid. For example, the absence of prion pro- tein (PrP) results in exacerbated EAE disease (Tsutsui et al., 2008; Gourdain et al., 2012; Hu et al., 2010) indicating a role for PrP in the modulation of cellular immune responses. Genetic deletion of regions encoding other amyloid-forming proteins including tau (Weinger et al., 2012) and serum amyloid P component (Ji et al., 2012) also results in more severe EAE disease. Furthermore, recent work reveals that ex- ogenous administration of peptide amyloids reduces EAE clinical sever- ity. For example, amyloids formed from Alzheimer's β 1-40 and 1-42 peptides reduce EAE clinical scores and histopathological signs of in- flammation (Grant et al., 2012). Additionally, amyloid fibril-forming hexapeptides reduce paralysis, inflammatory foci and serum IL-6 levels (Kurnellas et al., 2013). Collectively these data imply that amyloids can reduce inflammatory autoimmune processes. Multiple studies have suggested that PrP has an anti-inflammatory role in EAE pathogenesis. However, there are differing reports as to the mechanism by which PrP modulates the disease. It has been report- ed that in the absence of PrP, there is increased T cell infiltration in the CNS and that PrP -/- T cells have an increased myelin oligodendrocyte glycoprotein (MOG) specific proliferative capacity ex vivo (Tsutsui et al., 2008; Ingram et al., 2009; Hu et al., 2010). Furthermore, PrP has been implicated in T cell activation, differentiation, and survival in EAE (Hu et al., 2010), suggesting a role in mediating T cell effects in EAE. Con- versely, another study reported that MOG-challenged PrP -/- T cells from EAE mice had proliferation capacity and cytokine production that was similar to that of wild type T cells and attributed the exacerbation of EAE in PrP -/- animals to the absence of PrP in the CNS (Gourdain et al., 2012). Nevertheless, in all previous reports, the absence of PrP worsened EAE clinical disease, suggesting a protective role for the pro- tein in regulating pathogenesis. Journal of Neuroimmunology 298 (2016) 42–50 ⁎ Correspondence author. E-mail address: allison.kraus@nih.gov (A. Kraus). http://dx.doi.org/10.1016/j.jneuroim.2016.06.010 0165-5728/© 2016 Published by Elsevier B.V. Contents lists available at ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim