Molecular neuropathology of transgenic mouse models of Down syndrome

Abstract

Down syndrome (DS) is a complex, clinically heterogeneous disorder which shows both impairment of neurodevelopement and the neurodegenerative changes of Alzheimer's disease (AD). The phenotype of DS is caused by triplication of chromosome 21 and transgenic mouse models have been developed, and are being created, that carry single genes and chromosomal segments to excess. For example, transgenic mice containing additional copies of the amyloid precursor protein (APP) gene, have been useful in producing the Aβ deposition characteristic of AD and DS, but not the cytoskeletal changes that are the hallmarks of these human disorders. Such models are useful in replicating aspects of pathogenesis and allow for the testing of therapeutic agents to restore impaired function. Segmental trisomic mouse models, which survive to adulthood and possess three copies of multiple genes responsible for the DS phenotype, such as Ts1Cje and Ts65Dn, have been used to explore aspects of neurodevelopment and neurodegeneration. These animal models show some but not all the pathological, biochemical, and transcriptional changes seen in DS. They also have the advantage of allowing for the testing of therapeutic agents to restore impaired function. Analysis of the transcriptome and proteome of fetal and adult DS indicates that there is a complex relationship between gene dosage, gene and protein expression, and that data from animal models will need to be compared and evaluated in the light of data obtained from DS tissue.