Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation
Michael P Kurnellas1, Chris M Adams, Raymond A Sobel
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305-5316, USA.
Abstract:
The amyloid-forming proteins tau, αB 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 αB 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, we showed 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, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-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.
Insights
Amyloid fibrils derived from proteins like tau show therapeutic potential for multiple sclerosis (MS). These peptides reduce inflammation and paralysis in models of MS, suggesting a novel treatment approach for neuroinflammatory disorders.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Proteins like tau, alpha B crystallin, and amyloid P protein are present in multiple sclerosis (MS) lesions.
- Previous studies indicated therapeutic effects of amyloidogenic peptides from alpha B crystallin (HspB5) and amyloid beta in experimental autoimmune encephalomyelitis (EAE), a model for MS.
Purpose of the Study:
- To investigate the molecular mechanisms behind the therapeutic effects of amyloidogenic peptides in MS models.
- To evaluate a set of six-amino-acid amyloidogenic peptides for anti-inflammatory and therapeutic properties in EAE.
Main Methods:
- Administration of various six-amino-acid amyloidogenic peptides (from tau, amyloid beta A4, prion protein, HspB5, amylin, serum amyloid P, insulin B chain) to EAE models.
- Measurement of serological levels of interleukin-6 and assessment of paralysis.
- Analysis of protein precipitation by tau 623-628 fibrils.
Main Results:
- The tested amyloidogenic peptides demonstrated anti-inflammatory effects.
- These peptides significantly reduced interleukin-6 levels and attenuated paralysis in EAE models.
- Tau 623-628 fibrils were found to precipitate 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, indicating biological activity.
Conclusions:
- Amyloidogenic peptides, particularly those derived from tau, exhibit therapeutic potential for multiple sclerosis and other neuroinflammatory conditions.
- The chaperone function of amyloid fibrils correlates with their therapeutic efficacy.
- Amyloid fibrils act as active biological agents, suggesting a novel therapeutic strategy for neuroinflammation.
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