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Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps
Published on: August 14, 2016
Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing
M Britschgi1, C E Olin, H T Johns
1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
Summary
Natural antibodies targeting toxic beta-amyloid (Abeta) species decline with age and Alzheimer's disease (AD). These antibodies, found in humans and primates, show protective effects against Abeta toxicity, suggesting a potential preventive strategy for AD.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Alzheimer's disease (AD) is linked to various beta-amyloid (Abeta) forms.
- Natural human antibodies against Abeta exist, but their population-level characteristics are poorly understood.
- Current AD therapies include antibodies targeting Abeta peptides.
Purpose of the Study:
- To investigate the presence, diversity, and function of natural antibodies against Abeta and related amyloidogenic peptides in humans and non-human primates.
- To determine how antibody reactivity against Abeta species changes with age and AD progression.
- To assess the neuroprotective potential of naturally occurring and induced antibodies against Abeta toxicity.
Main Methods:
- Peptide microarrays were used to screen plasma and cerebrospinal fluid from AD patients and healthy controls.
- Antibody reactivity was analyzed against various Abeta species, including oligomeric, pyroglutamate, and oxidized forms.
- IgG isolation and in vitro assays were performed to evaluate the neuroprotective effects of antibodies.
- Aged vervet monkeys were used to study natural antibody patterns and immune responses after Abeta immunization.
Main Results:
- Natural antibodies against toxic Abeta and non-Abeta amyloid species were detected in human plasma and cerebrospinal fluid across a wide age range.
- Antibody reactivity was highest against oligomeric Abeta and modified residues; IgG levels specific for oligomeric Abeta1-42 decreased with age and AD.
- Antibodies from both AD patients and healthy controls demonstrated neuroprotective capabilities against Abeta toxicity in vitro.
- Vervet monkeys exhibited similar antibody patterns to humans and developed cross-reactive antibodies against mutant Abeta peptides after immunization.
Conclusions:
- Conformation-specific, cross-reactive antibodies may offer protection against toxic amyloidogenic peptides.
- Declining natural antibody levels with age and AD suggest a potential role in disease pathogenesis.
- Harnessing these natural antibodies, either by stimulation or passive administration, could represent a novel preventive strategy for Alzheimer's disease.
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