Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes

Abstract

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish if this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

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

“…Thus, three-copies of APP are sufficient and necessary to drive AD pathogenesis both in people who have and don't have DS. Consistent with this, a third copy of APP causes a 1.5-fold or higher level of full-length APP and its cleavage products in the adult brain of people that have DS and in preclinical mouse models (Cheon et al, 2008 ; Lana-Elola et al, 2021 ). However, from what age and in which cell types this gene is dosage-sensitive is unclear, as a previous report suggested that APP protein levels are not raised in the young adult brain in a preclinical model of DS (Choi et al, 2009 ).…”

“…The Dp(16)1Yey mouse model of DS also exhibits raised levels of App mRNA, FL-APP, CTFs, and Aβ in the cortex and hippocampus from as young as 4-months, increasing further by 19-months (Lana-Elola et al, 2021 ). Importantly, the increase in abundance of CTF was greater than the 1.5-fold increase that would be predicted to occur because of an extra copy of App ; the mechanism for this is not understood and may have considerable implications for the development of AD primary prevention therapy for people who have DS.…”

“…Furthermore, γ-secretase inhibition leads to increased production of CTFs (Netzer et al, 2010 ), which have been implicated in enlargement of endosomes in DS, contributing to perturbed neuronal transport (Filippone and Praticò, 2021 ). Given recent data indicating particularly highly elevated levels of this fragment in people with DS and preclinical DS mouse models (Lana-Elola et al, 2021 ), modulation of γ-secretase in people who have DS should be approached with caution.…”

“…Notably, both the Tc1 and Dp(16)1Yey mouse model contain an additional copy of USP25 (Gribble et al, 2013 ) and the gene is significantly upregulated in the adult hippocampus of the Tc1 model (Granno et al, 2019 ). However, raised levels of full-length APP are not consistently observed in the Tc1 brain or elevated above 1.5-fold in the Dp(16)1Yey model (which also contains 3-copies of App ), and raised levels of BACE1 are not observed in either model compared to euploid controls (Wiseman et al, 2018 ; Lana-Elola et al, 2021 ). Additional preclinical studies to understand the role of three-copies of USP25 are required to unravel this complexity.…”

“…Loss of BFCNs was associated with a compensatory effect in the 12-month Ts65Dn brain, whereby remaining hippocampal neurons had increased ChAT activity compared to younger mice of the same genotype (Seo and Isacson, 2005 ). The Ts2Cje model exhibits a loss of BFCNs in the MSN at 9-months of age (Jiang et al, 2016 ) and the Dp(16)1Yey model exhibits loss of BFCNs in the MSN, entorhinal cortex and locus coeruleus in an age-dependent manner, with significant loss seen at 16-months, but not 4-months (Lana-Elola et al, 2021 ).…”