Dissecting Alzheimer disease in Down syndrome using mouse models

Abstract

Down syndrome (DS) is a common genetic condition caused by the presence of three copies of chromosome 21 (trisomy 21). This greatly increases the risk of Alzheimer disease (AD), but although virtually all people with DS have AD neuropathology by 40 years of age, not all develop dementia. To dissect the genetic contribution of trisomy 21 to DS phenotypes including those relevant to AD, a range of DS mouse models has been generated which are trisomic for chromosome segments syntenic to human chromosome 21. Here, we consider key characteristics of human AD in DS (AD-DS), and our current state of knowledge on related phenotypes in AD and DS mouse models. We go on to review important features needed in future models of AD-DS, to understand this type of dementia and so highlight pathogenic mechanisms relevant to all populations at risk of AD.

Keywords: APP; Alzheimer disease; Down syndrome; mouse models; trisomy 21.

Figure 1

Human chromosome 21 (Hsa21), orthologous mouse chromosomes (Mmu), and key mouse models of Down syndrome. Diagram representing Hsa21 and its alignment with syntenic regions on Mmus 16, 17, and 10. The orange circle represents the human centromere and mouse models are color-coded and aligned according to the chromosomal segment for which they are trisomic. Numbers in brackets represent the number of protein-coding Hsa21 orthologous genes within each region or mouse model, according to Ensembl release 79 and the breakpoints published in papers referenced here. The Tc1 mouse is the only model which carries Hsa21, though genomic rearrangements and deletions (indicated by breaks in the chromosome) mean the mouse is functionally trisomic for only ~75% of Hsa21 genes (Gribble et al., 2013). All other mouse models carry duplications of mouse orthologues. The Dp1(16)Yey;Dp1(17)Yey;Dp1(10)Yey (or Ts1Yey;Ts3Yey;Ts2Yey) mouse was generated by crossing together three partial trisomy models (Yu et al., 2010a) and spans the entirety of the Hsa21-syntenic regions. The Ts65Dn mouse (Davisson et al., 1993) contains a freely segregating segment of Mmu16, however it is also trisomic for 43 extra protein-coding genes on the centromeric section of Mmu17 that are not relevant to DS (indicated by an asterisk (^*) and accompanying text box; Duchon et al., ; Reinholdt et al., 2011). The Ts1Cje mouse (Sago et al., 1998) also contains a monosomy of eight protein-coding genes on Mmu12, irrelevant to the DS phenotype (indicated by “#” and accompanying text box. Gene numbers are based on Ensembl release 79, compared to the original seven monosomic genes detailed in Duchon et al., 2011). Other mice are Ts1Rhr or Dp1(16)Rhr mice (Olson et al., 2004); Ts1Yah mice (Pereira et al., 2009); Ts3Yah (previously published as Ts2Yah; Brault et al., 2015); and Ts4Yah mice (previously published as Ts3Yah mice; Herault et al., 2009). Other useful examples of mouse models include the Ts43H model (not shown) which is partially trisomic for Mmu17 including some genes with ortholog on Hsa21 (Vacík et al., 2005). The scale is in megabase pairs (Mb).