Amyloid Fibrils Composed of Hexameric Peptides Attenuate Neuroinflammation

Abstract

Amyloid forming proteins Tau, alpha B crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein, alpha B crystallin(HspB5), and from amyloid β fibrils, characteristic of Alzheimer’s disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P (SAP), and insulin B chain were shown to be anti-inflammatory, capable of reducing serological levels of IL-6, and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of Tau 623–628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.

Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease

“…amyloid fibrils | B-1a lymphocytes | experimental autoimmune encephalomyelitis | immune suppression | IL-10 A myloid fibrils, composed of hexapeptides, when injected into the peritoneum of mice stimulate an immune-suppressive response of sufficient magnitude to reduce the paralytic signs of experimental autoimmune encephalomyelitis (EAE) (1,2). Analysis of the differential gene-expression pattern in peripheral blood mononuclear cells revealed the amyloidogenic peptides (e.g., Tau 623-628) induced a type 1 interferon (IFN) response.…”

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

“…In a 2013 article, we showed that hexapeptides that formed amyloid fibrils would suppress ongoing EAE. We showed that hexapeptides derived from β-amyloid, tau, prion protein, amylin and cryab all suppressed EAE (91).…”

“…The amyloid structures bind inflammatory mediators in plasma (89)(90)(91). Amyloid hexapeptide structures elicit a type 1 interferon response (93).…”

No quiet surrender: molecular guardians in multiple sclerosis brain

“…The hexapeptides bind a set of proinflammatory mediators in plasma, including acute-phase reactants and complement components. Administration of this amyloid-forming hexapeptide quickly lowers inflammatory cytokines in plasma such as IL-2 and IL-6, which are highly expressed in both acute and chronic MS lesions (31,41,86). The beneficial properties of amyloid-forming hexapeptides provide a potential new therapeutic direction.…”

“…Numerous phase 3 trials using these strategies have failed (90,91). Could amyloid molecules have a different role in MS (30,31)? Research on MS and its animal models point in this direction.…”