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

Abstract

Full-length Aβ1-42 and Aβ1-40, N-truncated pyroglutamate Aβ3-42 and Aβ4-42 are major variants in the Alzheimer brain. Aβ4-42 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 Aβ4-x and pyroglutamate Aβ3-X mitigated neuron loss in Tg4-42 mice expressing Aβ4-42 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 Aβ4-42. NT4X reduced pyroglutamate Aβ3-x, Aβx-40 and Thioflavin-S positive plaque load after passive immunization of 5XFAD mice. Aβ1-x and Aβx-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 Aβ starting with position four in addition to pyroglutamate Aβ3-x is a relevant target to fight Alzheimer’s disease.

Transgene integration causes RARB downregulation in homozygous Tg4–42 mice

“…Otherwise, therapeutic intervention studies with a monoclonal antibody or with enriched housing conditions were able to reduce hippocampal neuron loss and showed a rescue of spatial reference memory deficits in homozygous Tg4-42 mice. These data would rather indicate that the observed phenotype of homozygous Tg4-42 mice is caused by the Aβ4-42 transgene 7,10 . Another conclusion from the current work is that it should be obligatory to analyse a possible treatment effect in more than one Alzheimer's disease mouse model.…”

“…Additionally, this increased physical activity caused decreased neuron loss which resulted in a higher number of CA1 pyramidal cells 7 . A weekly treatment with the full-length or Fab fragment of a monoclonal antibody directed against Aß4-42 also showed the ability to completely rescue spatial reference memory deficits and significantly stabilized neuron numbers in 6 month old homozygous Tg4-42 mice 10 .…”

“…hippocampal neuron loss is only observed in a few models [4][5][6][7][8][9] . For this reason, we further characterized the previously described Tg4-42 mouse model, as it develops neuronal loss and therefore represents a promising model for the development of new drugs or drug efficacy studies 10 . Homozygous Tg4-42 mice are characterized by an age depended, massive CA1 pyramidal neuronal loss in the hippocampus.…”

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

“…Bayer and co‐workers have found that Aβ 4‐40 and Aβ 4‐42 possessed similar toxicity comparable to Aβ 1‐42 in vitro and in model mice . By utilizing a monoclonal antibody (NT4X) for Aβ 4‐ x , they confirmed the existence of Aβ 4‐ x in 5XFAD mice as well as the benefits of treating 5XFAD mice with NT4X . These results suggested that Aβ 4‐ x is worthy of a deep exploration for AD treatment.…”

Genetic rodent models of brain disorders: Perspectives on experimental approaches and therapeutic strategies

“…For example, in the field of AD, potential mechanisms of disease are still hotly debated with the relative contributions of amyloid plaques and neurofibrillary tangles or other pathways still uncertain (Ballatore, Lee, & Trojanowski, ; Selkoe & Hardy, ). Preclinical proof‐of‐concept testing for antibody‐based therapies largely addressed the plaque burden and molecular load of amyloid‐β within the brains of AD‐related mouse models (Bard et al, ), with some studies also showing therapeutic improvement in learning and memory performance tasks (Antonios et al, ; Dodart et al, ; Wang, Yu, Liu, Zhao, & Xu, ). However, some of the animal model data demonstrated that acute intervention led to changes in learning and memory performance without an appreciable effect on amyloid‐β burden (Dodart et al, ), thereby dissociating the relationship between a pathological hallmark implicated in AD and the expected behavioral improvement.…”