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

Full-length A beta 1-42 and A beta 1-40, N-truncated pyroglutamate A beta 3-42 and A beta 4-42 are major variants in the Alzheimer brain. A beta 4-42 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 A beta 4-x and pyroglutamate A beta 3-X mitigated neuron loss in Tg4-42 mice expressing A beta 4-42 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 A beta 4-42. NT4X reduced pyroglutamate A beta 3-x, A beta x-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. A beta 1-x and A beta x-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 A beta starting with position four in addition to pyroglutamate A beta 3-x is a relevant target to fight Alzheimer's disease