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Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

Bibliographic

Year of Publication:
2000
Contact PI Name:
Howard L. Weiner
Contact PI Affiliation:
Center for Neurologic Diseases, Harvard Institutes of Medicine, Boston, Massachusetts, USA
Co-Authors:
Cynthia A. Lemere, Ruth Maron, Edward T. Spooner, Trelawney J. Grenfell, Chica Mori, Shohreh Issazadeh, Dennis J. Selkoe
Primary Reference (PubMED ID):
Funding Source:
National Institutes of Health (NIH)
Foundation for Neurologic Diseases
Study Goal and Principal Findings:

Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. Was hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, were treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of approximately 5 and approximately 12 months with human Abeta synthetic peptide mucosally each week. We found significant decreases in the cerebral Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. This results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Immunotherapy(active)
Therapeutic Agent:
beta Amyloid Peptide 1-40
Therapeutic Target:
beta Amyloid Peptide

Animal Model

Model Information:
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Histopathology
beta Amyloid Deposits
beta Amyloid Load
Activated Microglia
Activated Astrocytes
Dystrophic Neurites
Biochemical
Cytokines
Interleukin 4 (IL-4)
Interleukin 10 (IL-10)
Tumor Growth Factor beta (TGF beta)
Brain-Guanidine Soluble beta Amyloid Peptide 40
Brain-Guanidine Soluble beta Amyloid Peptide 42
Immunochemistry
Neuritic Dystrophy
Glial Fibrillary Acidic Protein (GFAP)
Activated Astrocytes
CD45
CD11b
Amyloid Precursor Protein (APP)
Tau Protein
Synaptophysin
CD8
Brain-Interferon (IFN) gamma
Interleukin 10 (IL-10)
Interleukin 4 (IL-4)
Interleukin 2 (IL-2)
CD4
Complement C1q
Brain-beta Amyloid Deposits
Interferon (IFN) gamma
Cell Biology
Mononuclear Cells
Immunology
Cellular Immune Response
Interferon (IFN) gamma Production
T Cell Response
Antibody Target Specificity
IgG Antibody Titers
Pharmacodynamics
Target Engagement (Reduction beta Amyloid Peptides-Brain)