Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches

Abstract

There are an estimated 6 million people with Down syndrome (DS) worldwide. In developed countries, the vast majority of these individuals will develop Alzheimer's disease neuropathology characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles within the brain, which leads to the early onset of dementia (AD-DS) and reduced life-expectancy. The mean age of onset of clinical dementia is ~55 years and by the age of 80, approaching 100% of individuals with DS will have a dementia diagnosis. DS is caused by trisomy of chromosome 21 (Hsa21) thus an additional copy of a gene(s) on the chromosome must cause the development of AD neuropathology and dementia. Indeed, triplication of the gene APP which encodes the amyloid precursor protein is sufficient and necessary for early onset AD (EOAD), both in people who have and do not have DS. However, triplication of other genes on Hsa21 leads to profound differences in neurodevelopment resulting in intellectual disability, elevated incidence of epilepsy and perturbations to the immune system. This different biology may impact on how AD neuropathology and dementia develops in people who have DS. Indeed, genes on Hsa21 other than APP when in three-copies can modulate AD-pathogenesis in mouse preclinical models. Understanding this biology better is critical to inform drug selection for AD prevention and therapy trials for people who have DS. Here we will review rodent preclinical models of AD-DS and how these can be used for both in vivo and ex vivo (cultured cells and organotypic slice cultures) studies to understand the mechanisms that contribute to the early development of AD in people who have DS and test the utility of treatments to prevent or delay the development of disease.

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

“…Interestingly, this decrease was consistently distributed bilaterally and aligned with the plausible anatomical regions. While this subtle decrease is not statistically significant, it warrants further study with larger groups of animals, and/or in older age or in models combining DS with Alzheimer's pathology where the confluence of T1 and neurodegeneration might be more pronounced ( Farrell et al, 2022 ).…”

Cognitive and molecular characterization of the Ts66Yah murine model of Down syndrome: deepening on hippocampal changes associated with genotype and aging

“…The genetic validity of available murine models for the study of DS phenotype has been a topic of strong debate in the last decade [3,[33][34][35][36]. To improve the representation of DS human genotype and phenotype in mice, Herault and colleagues developed new line named Ts66Yah, derived from the Ts65Dn lineage but no longer carrying the duplicated centromeric part of Mmu17, [20].…”

Liver X Receptor Regulation of Glial Cell Functions in the CNS

“…There are several mouse models and cell lines that are used extensively to study AD. Some overexpress APP and some express the human APOE4 variant, which is associated with AD [ 76 ]. In the APP/PS1 transgenic mouse, a mouse model in which there is of buildup Aβ in the brain, loss of LXRα or LXRβ results in increased amyloid plaque burden [ 52 ].…”