OO022 - DISCOVERY OF A UNIQUE EPITOPE IN THE N-TERMINUS OF PYROGLUTAMATE ABETA FOR USE AS A VACCINE AGAINST ALZHEIMER’S DISEASE (ID 265)

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tbayer@gwdg.de
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Abstract

Aims

Pyroglutamate Abeta (pE3) are abundantly present in the brain of Alzheimer’s disease (AD) patients, form stable oligomers, induce neurodegeneration in mouse models their potential as drug target has not been generally accepted in the past. We discovered a unique epitope in the N-terminus of Abeta pE3-X representing a valid target for active immunization. The therapeutic effect of this vaccine was evaluated using transgenic AD mouse models on the level of amyloid load and glucose metabolism in vivo, memory performance and neuron loss in the hippocampus.

Methods

Transgenic mice (5XFAD, Tg4-42), Morris water maze, neuron count, 18F-Florbetaben-PET/MRI imaging, 18F-FDG-PET/MRI imaging, immunostaining, in vivo amyloid imaging, in vivo glucose uptake

Results

The crystal structures of the binding pocket of TAPAS antibodies revealed that bound N-terminal region of Abeta adopted a novel structure, not related to any fibrillar or amyloid associated conformations reported so far. The crystal structure enabled the design of a novel Abeta peptide epitope for use as a vaccine. Active immunization of the AD mouse model 5XFAD resulted in a striking reduction in amyloid-plaque load in brain tissue by both immunostaining and in vivo 18F-Florbetaben-PET retention analysis. Moreover, using 18F-FDG-PET/MRI imaging we could show a rescue of glucose metabolism after active immunization. In addition, active immunization of the AD mouse model Tg4-42 rescued learning and memory deficits, as well as loss of neurons in the hippocampus. Comparable positive therapeutic indications were also seen after TAP01 antibody passive immunization in both animal models.

Conclusions

The TAPAS epitope is a promising novel vaccination against AD.

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