Intracranial administration of deglycosylated C-terminal-specific anti-Aβ antibody efficiently clears amyloid plaques without activating microglia in amyloid-depositing transgenic mice
| Autor: | Niki C Carty, Arnon Rosenthal, Dave Morgan, Jaume Pons, Donna M. Wilcock, Paul E. Gottschall, Marcia N. Gordon, Jan Grimm, Victoria Ronan |
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| Rok vydání: | 2006 |
| Předmět: |
Genetically modified mouse
Pathology medicine.medical_specialty Amyloid Immunology lcsh:RC346-429 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine Amyloid precursor protein lcsh:Neurology. Diseases of the nervous system 030304 developmental biology 0303 health sciences Microglia biology business.industry Research General Neuroscience medicine.disease Molecular biology 3. Good health medicine.anatomical_structure Neurology biology.protein Immunohistochemistry Cerebral amyloid angiopathy Antibody business 030217 neurology & neurosurgery Immunostaining |
| Zdroj: | Journal of Neuroinflammation, Vol 3, Iss 1, p 11 (2006) Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| Popis: | Background Antibodies against the Aß peptide clear Aß deposits when injected intracranially. Deglycosylated antibodies have reduced effector functions compared to their intact counterparts, potentially avoiding immune activation. Methods Deglycosylated or intact C-terminal specific high affinity anti-Aβ antibody (2H6) were intracranially injected into the right frontal cortex and hippocampus of amyloid precursor protein (APP) transgenic mice. The untreated left hemisphere was used to normalize for the extent of amyloid deposition present in each mouse. Control transgenic mice were injected with an antibody against a drosophila-specific protein (amnesiac). Tissues were examined for brain amyloid deposition and microglial responses 3 days after the injection. Results The deglycosylated 2H6 antibody had lower affinity for several murine Fcγ receptors and human complement than intact 2H6 without a change in affinity for Aß. Immunohistochemistry for Aβ and thioflavine-S staining revealed that both diffuse and compact deposits were reduced by both antibodies. In animals treated with the intact 2H6 antibody, a significant increase in Fcγ-receptor II/III immunostaining was observed compared to animals treated with the control IgG antibody. No increase in Fcγ-receptor II/III was found with the deglycosylated 2H6 antibody. Immunostaining for the microglial activation marker CD45 demonstrated a similar trend. Conclusion These findings suggest that the deglycosylated 2H6 is capable of removing both compact and diffuse plaques without activating microglia. Thus, antibodies with reduced effector functions may clear amyloid without concomitant immune activation when tested as immunotherapy for Alzheimer's disease. |
| Databáze: | OpenAIRE |
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