Protein Misfolding: Therapeutic Implications

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Presentation transcript:

Protein Misfolding: Therapeutic Implications Opportunities for Therapeutic and Diagnostic Development for Degenerative Diseases Charles Glabe, Ph.D.

Overview Conformation-dependent antibodies specifically recognize toxic soluble amyloid oligomers and distinguish them from natively folded protein, denatured monomer and amyloid fibrils. This provides a means of specifically targeting soluble amyloid oligomers through immunization. Immunization may be an effective treatment for AD and other degenerative diseases.

Soluble amyloid oligomers are suspected to be a causative agent in a broad range of degenerative diseases disease. Alzheimer’s disease Type II diabetes Parkinson’s disease Huntington’s disease Prion (Mad Cow’s) disease Serum amyloidosis Familial Amyloid Polyneuropathy Macula Degeneration. Amyltropic Lateral Sclerosis Inclusion Body Myositis Idiopathic Cardiomyopathy

Toxic Soluble Oligomers Soluble Amyloid Oligomers are a Common Intermediate in Amyloid Fibril Formation. Toxic Soluble Oligomers

Antigen Preparation Au Au Au Au Au (Micelle mimics) A Aß A A A SR

Anti-Oligomer antibody specificity Dot blot ELISA Oligomers Monomer Fibrils Oligomers Monomer and Fibrils

Characteristics of immune response to Aß-gold oligomer mimics. The immune response is specific. No immunoreactivity against “normal” sequence dependent Aß epitopes after 12 injections. The immune response is long lasting: Titer does not drop significantly within 6 months after vaccination. Adjuvant is not required for high titer immune response.

Anti-Oligomer antibody recognizes soluble oligomers from all other types of amyloids.

Anti-Oligomer neutralizes the toxicity of all types of amyloid oligomers. No antibody Anti-Oligomer Pre-immune

Summary Immunization with a molecular mimic of Aß micelles produces a polyclonal antibody (Anti-Oligomer), that is specific for the soluble, high molecular weight micellar oligomeric intermediate that is common to all amyloids tested. Anti-Oligomer does not recognize APP, soluble monomeric A or fibrillar peptides. Anti-Oligomer neutralizes the toxicity of all types of oligomers. The fact that soluble amyloid oligomers have a common structure suggests that they share a common mechanism of toxicity and pathogenesis.

Anti-Oligomer immuno-reactivity in human AD brain. Red: Anti-Oligomer Green: Thio S staining of amyloid fibers

Oligomer levels in soluble extracts of human brain.

Summary Anti-Oligomer immunoreactivity is elevated in AD brain. Anti-Oligomer stains small, focal deposits in AD and Tg mouse brain that are distinct from Thio-S positive and diffuse plaques. Anti-Oligomer immunoreactivity is elevated in AD brain. Oligomeric Aß represents a small fraction of the total Aß.

Summary Vaccination with Aß-gold oligomer molecular mimics may be as effective as preventing amyloid accumulation as fibrillar Aß, but yet it may avoid the inflammatory complications associated with the first generation of Alzheimer’s disease vaccine.

Potential Applications The Aß oligomer molecular mimic antigen may be useful for development of a specific vaccine that avoids autoimmune and inflammatory complications. Anti-Oligomer antibody may be useful as a diagnostic tool to determine the levels of the soluble oligomers in biological fluids. The anti-Oligomer antibody may be a valuable specific surrogate marker to evaluate the therapeutic effectiveness of agents that are designed to decrease or eliminate the neurotoxic amyloid. Anti-Oligomer antibody may be useful for high-throughput screening for drugs that inhibit oligomer formation.

Opportunities for Therapeutic and Diagnostic Development Diabetes Type II Alzheimer’s Disease Mad Cow’s Disease Parkinson’s Disease Huntington’s Disease Serum amyloidosis Vaccine Drug Discovery Diagnostic X X X X X X X X X X X X X X X X X X A single focus on the common toxic oligomers provides a large number of opportunities for product development.

Dr. Rakez Kayed Dr. Saskia Milton Dr Noriko Kamei Dr. Yuji Yoshiike Dr. Ruby Chen Jennifer Thompson Erene Mina Collaborators: Dr. Andrea Tenner Dr. Frank LaFerla Dr. Liz Head Dr. Carl Cotman Supported NIH grants NS31230, AG00538, AG16573 and a grant from the Larry L. Hillblom foundation.