charles glabe, ph.d. - alz.washington.edu · •dr. carl cotman supported nih grants ns31230,...
TRANSCRIPT
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Protein Misfolding: Therapeutic Implications
Charles Glabe, Ph.D.
Opportunities for Therapeutic and Diagnostic
Development for Degenerative Diseases
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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.
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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
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Soluble Amyloid Oligomers are a Common Intermediate in Amyloid Fibril Formation.
Toxic Soluble
Oligomers
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Au
AuAu
Au
SRA
SRA
SRAß
SRA
SRA
SRA
SRA
SRA
Au
A
A
AA
Au
A
ßA
AA
Au
A
A
AAAu
A
A
AA
(Micelle mimics)
Antigen Preparation
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Oli
go
mer
s
Mo
no
mer
Fib
rils ELISA
Dot blot
Anti-Oligomer antibody specificity
Oligomers
Monomer and Fibrils
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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.
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Anti-Oligomer antibody recognizes soluble oligomers from all other types of amyloids.
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No antibody
Anti-Oligomer
Pre-immune
Anti-Oligomer neutralizes the toxicity of
all types of amyloid oligomers.
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• 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.
Summary
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Red: Anti-
Oligomer
Green: Thio S
staining of
amyloid fibers
Anti-Oligomer immuno-reactivity in human AD brain.
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Oligomer levels in soluble extracts of human brain.
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• 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
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• 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.
Summary
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• 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.
Potential Applications
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Opportunities for Therapeutic and Diagnostic Development
1. Vaccine
2. Drug
Discovery
3. Diagnostic
Diabetes
Type II
Alzheimer’s
Disease
Mad Cow’s
Disease
Parkinson’s
Disease
Huntington’s
Disease
A single focus on the common toxic oligomers provides a large
number of opportunities for product development.
X X X X X
X X X X X
X X X X X
Serum
amyloidosis
X
X
X
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• 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.