Gareth Hall, United Kingdom
University of Leicester Molecular and Cell BiologyAuthor Of 1 Presentation
TAPAS-PART 2: THERAPY EFFECTS OF HUMANIZED ANTIBODIES AND NOVEL VACCINE AGAINST TRUNCATED AMYLOID-PEPTIDES AMINO ACIDS (TAPAS)
Abstract
Aims
We have previously identified a mouse antibody (TAP01), which bound to non-plaque forms of Aβ and showed therapeutic potential in mouse models of Alzheimer’s disease (AD). Here, we report the development of novel humanized antibodies, the crystal structure of the binding pocket and the discovery of a novel epitope representing a vaccine for active immunization. The therapeutic effects of these new therapeutic approaches were evaluated using two transgenic Alzheimer mouse models on the level of synaptic activity, plaque load, memory and neuron loss.
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
Crystal structures of N-truncated Abeta revealed that bound N-terminal region of Aβ adopted a novel structure, not related to any fibrillar or amyloid associated conformations reported and accounts for the non-plaque specificity of TAP01. The crystal structures enabled the design of a novel Abeta peptide epitope used 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 in vivo glucose 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, and rescued loss of neurons in the hippocampus. Comparable positive therapeutic indications were also seen after TAP01 antibody passive immunization in both animal models.
Conclusions
Active immunization with the novel epitope has therapeutic effects in vivo.