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Receptor-Mediated Abeta Amyloid Antibody Targeting to Alzheimer’s Disease Mouse Brain
- Source :
- Molecular Pharmaceutics. 8:280-285
- Publication Year :
- 2010
- Publisher :
- American Chemical Society (ACS), 2010.
-
Abstract
- The goal of this work is the reduction in the Abeta amyloid peptide burden in brain of Alzheimer’s disease (AD) transgenic mice without the concomitant elevation in plasma Abeta amyloid peptide. An anti-Abeta amyloid antibody (AAA) was re-engineered as a fusion protein with a blood-brain barrier (BBB) molecular Trojan horse. The AAA was engineered as a single chain Fv (ScFv) antibody, and the ScFv was fused to the heavy chain of a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), and this fusion protein was designated cTfRMAb-ScFv. The cTfRMAb-ScFv protein penetrates mouse brain from blood via transport on the BBB TfR, and the brain uptake is 3.5 % of injected dose/gram brain following an intravenous administration. Double transgenic APPswe,PSEN1dE9 mice were studied at 12 months of age. The mice were shown to have extensive Abeta amyloid plaques in cerebral cortex based on immunocytochemistry. The mice were treated every 3–4 days by intravenous injections of either saline or the cTfRMAb-ScFv fusion protein at an injection dose of 1 mg/kg for 12 consecutive weeks. The brain Aβ1–42 concentration was reduced 40% in the fusion protein treated mice, without any elevation in plasma Aβ1–42 concentration. No cerebral micro-hemorrhage was observed in the treated mice. These results show that brain-penetrating antibody pharmaceutics can be developed for brain disorders such as AD following the re-engineering of the antibody as a fusion protein that is transported across the BBB via receptor-mediated transport.
- Subjects :
- Male
Genetically modified mouse
Amyloid
Immunocytochemistry
Pharmaceutical Science
Enzyme-Linked Immunosorbent Assay
Mice, Transgenic
Plaque, Amyloid
Transferrin receptor
Blood–brain barrier
Article
Mice
Alzheimer Disease
Receptors, Transferrin
Drug Discovery
medicine
Animals
Amyloid beta-Peptides
biology
Chemistry
Antibodies, Monoclonal
Brain
medicine.disease
Immunohistochemistry
Molecular biology
Fusion protein
medicine.anatomical_structure
Blood-Brain Barrier
biology.protein
Molecular Medicine
Alzheimer's disease
Antibody
Subjects
Details
- ISSN :
- 15438392 and 15438384
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Molecular Pharmaceutics
- Accession number :
- edsair.doi.dedup.....4d0d89817ee05fae666266c4d9e9f063