Accumulation of amyloid fibrils correlates with neurodegeneration in various brain diseases, but the biological role of the fibrils is unclear. Ourprevious experiments established that amyloidogenic peptides from the small heat shock protein, HspB5, and from Amyloid ? fibrils, characteristic of Alzheimer's disease, were therapeutic when administered systemically in experimental autoimmune encephalomyelitis (EAE), which models aspects of neuroinflammation in multiple sclerosis. The minimal structural units for the therapeutic amyloid fibrils are peptides as short as hexamers, which are capable of forming cross beta sheet steric zippers, but not the complex super secondary structures, torroids, cylindrins, and ? barrels, inherent in protein based amyloids that result in cellular cytotoxicity. The minimal fibrils are molecular chaperones, inhibiting protein aggregation in plasma, which reduces the gene expression of a spectrum of proinflammatory mediators. In addition, the amyloid fibrils are pinocytosed by neutrophils, resulting in net formation, which in turn results in the stimulation of plasmacytoid dendritic cells to secrete type 1 interferon. The latter activity is beneficial in diseases dominated by Th1 lymphocytes, but deleterious in indications in which Th17 responses are dominant. The aims of this proposal are to develop a clinical candidate by incorporating recent experimental results demonstrating that the amyloidogenic peptides composed of L- or D- acids form amyloid fibrils equivalently, are comparable molecular chaperones, and effective therapeutics. In addition, the polarity of the peptides does not have appreciable effect on their chaperone activity, but has been shown to reduce the rate of fibril formation, the resultant activation of neutrophils, and subsequent induction of type 1 interferon in vivo. The second aim of this proposal is to generate a set of antibodies specific for the lead peptide, both for the monomeric peptide and when it is part of an amyloid fibril, which can be used to determine the biological half-life and distribution of the peptide and amyloid fibril. The third aim focuses on the delivery of the peptides and fibrils. Forcommercialization the peptide analogs will need to be repeatedly injected, which can be practically accomplished using mechanical or osmotic pumps. The effective dose of a soluble amyloidogenic peptide will be determined using this technology in mice, which should segue into similar technology in larger animals.
Thesaurus Terms: Acids;Alpha-Crystallin B Chain;Alzheimer's Disease;Amino Acids;Amyloid;Amyloid Fibril Formation;Amyloid Fibrils;Amyloid Proteins;Animal Model;Animals;Anti-Inflammatory;Anti-Inflammatory Agents;Antibodies;Base;Beta Pleated Sheet;Biological;Biological Process;Brain Diseases;Cardiac;Cell-Mediated Cytolysis;Cells;Characteristics;Clinical;Commercialization;Complex;Cytokine;Dendritic Cells;Design;Disease;Dose;Drug Kinetics;Experimental Autoimmune Encephalomyelitis;Gene Expression;Genes;Half-Life;Heat Shock Proteins;In Vivo;Inflammation;Inflammatory;Interferon Type I;Interferon-Alpha;Interferons;Islet Amyloid Polypeptide;Lead;Lymphocyte;Mechanics;Mediator Of Activation Protein;Modeling;Molecular Chaperones;Monomer;Multiple Sclerosis;Mus;Nerve Degeneration;Nervous System Disorder;Neurodegenerative Disorders;Neuroinflammation;Neuropathology;Neutrophil;Neutrophil Activation;Paralysed;Peptide Analog;Peptides;Pharmacodynamics;Pinocytosis;Plasma;Principal Investigator;Production;Property;Protein Aggregation;Proteins;Public Health Relevance;Pump;Recombinant Interferon Beta-1b;Reperfusion Injury;Research Study;Response;Retinal Ischemia;Role;Route;Serological;Stroke;Structure;Tau Proteins;Technology;Therapeutic;Tissue-Specific Gene Expression;Tissues;Toxic Effect;Water Solubility;
