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Amyloid beta 4-42 in Alzheimer’s disease: Target, Therapy, Mechanism

dc.contributor.advisorBayer, Thomas A. Prof. Dr.
dc.contributor.authorAntonios, Gregory
dc.titleAmyloid beta 4-42 in Alzheimer’s disease: Target, Therapy, Mechanismde
dc.contributor.refereeJarry, Hubertus Prof. Dr.
dc.description.abstractengTargeting Aβ has recently been the main objective in Alzheimer’s disease therapeutic approaches. Passive immunization trials have encountered undesirable side effects but the therapy remains a promising option. Aβ4-x has not been previously considered as a target for AD immunotherapy. Tg4-42 mouse model has been recently established and validated as an advantageous research tool in AD. The current work deals with Aβ4-42 and explores its potential as a target, while elucidating therapeutic mechanism and crystallizing the NT4X Fab in complex with Aβ4-19 aiming to further reveal the structural basis of antibody: target affinity. In the present work, the novel monoclonal antibody NT4X specifically reacts with N-truncated Aβ at position 4 of Aβ. It binds N-truncated Aβ under native and denaturing conditions and rescues in vitro toxicity of Aβ4-42 and that of pyroglutamate AβpE3-42. The Fab fragment of the antibody was also able to prevent the in vitro toxicity caused by Aβ4-42 in rat primary cortical neuron cultures. Aβ4-42 intracerebroventricular injection into wildtype mice induced a behavioral deficit, shown as a reduction in alteration rate in a Y-Maze, which was prevented using the NT4X. The Fab fragment of the antibody, at a higher dosage, was also able to prevent the in vivo behavioral deficit in a replicate experiment.   The Tg4-42 homozygous mouse model, expressed Aβ4-42 and allows for is intraneuronal accumulation. At 6 months of age, the model already exhibits 50% neuronal loss in the CA1 region of the hippocampus and severe reference memory deficits in a Morris water maze. Preventative passive immunotherapy with the NT4X antibody and its Fab fragment was able to mitigate neuron loss significantly and rescue spatial memory deficits as compared to an isotype control group. Crystallization of the NT4X Fab in complex with Aβ4-19 has been successful. Diffraction data has been collected at 2.8 Å. Efforts to resolve the crystal structure of the complex are ongoing. Issues with antibody-target engagement in terms of affinity, species and conformation of Aβ bound may be dealt with before going to a clinical setting, with the help of information arising from the crystal structure of the NT4X Fab: Aβ4-19 complex.    de
dc.contributor.coRefereeDresbach, Thomas Prof. Dr.
dc.subject.engAlzheimer, Abeta, Immunotherapy, Tg4-42, transgenic micede
dc.affiliation.instituteMedizinische Fakultät

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