Alzheimer therapy with an antibody against N-terminal Abeta 4-X and pyroglutamate Abeta 3-X.

ABSTRACT

Full-length Aß1-42 and Aß1-40, N-truncated pyroglutamate Aß3-42 and Aß4-42 are major variants in the Alzheimer brain. Aß4-42 has not been considered as a therapeutic target yet. We demonstrate that the antibody NT4X and its Fab fragment reacting with both the free N-terminus of Aß4-x and pyroglutamate Aß3-X mitigated neuron loss in Tg4-42 mice expressing Aß4-42 and completely rescued spatial reference memory deficits after passive immunization. NT4X and its Fab fragment also rescued working memory deficits in wild type mice induced by intraventricular injection of Aß4-42. NT4X reduced pyroglutamate Aß3-x, Aßx-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Aß1-x and Aßx-42 plaque deposits were unchanged. Importantly, for the first time, we demonstrate that passive immunization using the antibody NT4X is therapeutically beneficial in Alzheimer mouse models showing that N-truncated Aß starting with position four in addition to pyroglutamate Aß3-x is a relevant target to fight Alzheimer's disease.