Comprehensive Characterization of the Pyroglutamate Amyloid-β Induced Motor Neurodegenerative Phenotype of TBA2.1 Mice

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is being intensively investigated using a broad variety of animal models. Many of these models express mutant versions of human amyloid-β protein precursor (AβPP) that are associated with amyloid-β protein (Aβ)-induced early onset familial AD. Most of these models, however, do not develop bold neurodegenerative pathology and the respective phenotypes. Nevertheless, this may well be essential for their suitability to identify therapeutically active compounds that have the potential for a curative or at least disease-modifying therapy in humans. In this study, the new transgenic mouse model TBA2.1 was explored in detail to increase knowledge about the neurodegenerative process induced by the presence of pyroglutamate modified human Aβ3-42 (pEAβ3-42). Analysis of the sensorimotor phenotype, motor coordination, Aβ pathology, neurodegeneration, and gliosis revealed formation and progression of severe pathology and phenotypes including massive neuronal loss in homozygous TBA2.1 mice within a few months. In contrast, the start of a slight phenotype was observed only after 21 months in heterozygous mice. These data highlight the role of pEAβ3-42 in the disease development and progression of AD. Based on the findings of this study, homozygous TBA2.1 mice can be utilized to gain deeper understanding in the underlying mechanisms of pEAβ3-42 and might be suitable as an animal model for treatment studies targeting toxic Aβ species, complementary to the well described transgenic AβPP mouse models.

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model

“…Female SOD1*G93A mice with a high copy number of the transgene were selected for stratified randomisation into equally groups. Housing of the animals was under the same terms at the animal facility of the Forschungszentrum Jülich as described previously [ 35 , 68 ].…”

“…The modified pole test [ 68 ] is a sensitive functional test to measure early changes in the motor behaviour of the SOD1*G93A mice. The following modifications were realised: The mice were placed with the head downwards instead of upwards on a vertical pole (height 50 cm, diameter 1.2 cm, rough-surfaced) and their movement downwards was rated.…”

A Novel Anti-inflammatory D-peptide Halts Disease Phenotype Progression in an Als Mouse Model

“…Female SOD1*G93A mice with a high copy number of the transgene were selected for strati ed randomisation into equally groups. Housing of the animals was under the same terms at the animal facility of the Forschungszentrum Jülich as described previously [41,35].…”

“…The modi ed pole test [41] is a sensitive functional test to measure early changes in the motor behaviour of the SOD1*G93A mice. The following modi cations were realised: The mice were placed with the head downwards instead of upwards on a vertical pole (height 50 cm, diameter 1.2 cm, rough-surfaced) and their movement downwards was rated.…”

Transgene integration causes RARB downregulation in homozygous Tg4–42 mice

“…Alzheimer's disease (AD) is the most common neurodegenerative disorder and mainly characterized by progressive neurodegeneration as well as extracellular accumulation of amyloid-ß protein (Aß) that is surrounded by dystrophic neurites and neurofibrillary tangles 1 . To gain deeper insight into the underlying disease mechanisms the use of AD animal models in research is highly relevant and thus far without alternative 2,3 . While cognitive deficits, amyloid deposits or neurofibrillary tangles and inflammation are observable in many AD mouse models, neurodegenerative pathology as characterized by e.g.…”