Reversal of Paralysis and Reduced Inflammation from Peripheral Administration of β-Amyloid in T _H 1 and T _H 17 Versions of Experimental Autoimmune Encephalomyelitis

Abstract

Abstractβ-amyloid-42 (Aβ42) and β-amyloid-40 (Aβ40), major components of senile plaque deposits in Alzheimer's disease (AD), are considered neurotoxic and pro-inflammatory. In multiple sclerosis (MS), Aβ42 is upregulated in brain lesions and damaged axons. Here we found, unexpectedly, that treatment with either Aβ42 or Aβ40 peptides reduced motor paralysis and brain inflammation in four different models of experimental autoimmune encephalomyelitis (EAE) with attenuation of motor paralysis, reduction of inflammatory lesions in the central nervous system (CNS), and suppression of lymphocyte activation. Aβ42 and Aβ40 treatments were effective in reducing ongoing paralysis induced with adoptive transfer of either autoreactive Th1 or Th17 cells. Highdimensional 14-parameter flow cytometry of peripheral immune cell populations after in vivo Aβ42 and Aβ40 treatment revealed substantial modulations in the percentage of lymphoid and myeloid subsets during EAE. Major pro-inflammatory cytokines and chemokines were reduced in the blood following Aβ peptide treatment. Protection conferred by Aβ treatment did not require its delivery to the brain: adoptive transfer with lymphocytes from donors treated with Aβ42 attenuated EAE in WT recipient mice and Aβ deposition in the brain was not detected in treated EAE mice by immunohistochemical analysis. In contrast to the improvement in EAE with Aβ-treatment, EAE was worse in mice with genetic deletion of the amyloid precursor protein. Therefore, in the absence of Aβ there is exacerbated clinical EAE disease progression. Since Aβ42 and Aβ40 ameliorate experimental autoimmune inflammation targeting the CNS, we might now consider its potential anti-inflammatory role in other neuropathological conditions.

Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

“…That amyloid forming peptides are immunosuppressive and therapeutic is counterintuitive to the manifold publications emphasizing their correlation with inflammation. However, we have observed similar effects when ␤ amyloid peptides are used as treatment for EAE (48) and currently are exploring the molecular basis for these effects.…”

A Journey in Science: The Privilege of Exploring the Brain and the Immune System

“…Moreover, Eisenberg and colleagues had shown that there was a minimal hexapeptide motif in these proteins that had sufficient energy to form β zipper structures and amyloid fibrils (84,85). An entrepreneurial PhD student, Jacqueline Grant, had shown that injection of β-amyloid peptides 1-40 or 1-42, thought to be pathogenic in Alzheimer's disease, were capable of suppressing EAE (86 (104,105). Proinsulin is at the top of the list of antigens that are targets of the autoimmune response in type 1 diabetes (104,105).…”

Profile of Lawrence Steinman

“…Given the association of amyloid proteins with neurodegenerative diseases, Steinman expected that administering amyloid proteins in the EAE model would exacerbate the inflammation. Instead, mice receiving an intravenous infusion of amyloid "started walking around" (13). Steinman was as surprised as anyone else, but he now sees a different role for amyloid proteins in MS. "If you look under the microscope at diseases like Alzheimer's or Parkinson's, you don't see much evidence of an inflammatory response.…”