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

Down syndrome (DS) is the most common condition with intellectual disability and is caused by trisomy of Homo sapiens chromosome 21 (HSA21). The increased dosage of genes on HSA21 is the cause for the initial neurodevelopmental disorder and for further development of cognitive decline, however the molecular mechanisms promoting brain pathology along ageing are still missing. One of the major challenges in the study of DS is the lack of reliable murine model able to accurately replicate genotypic and phenotypic aspects observed in humans along ageing. Preclinical studies in DS were pioneered using the Ts65Dn murine model, which despite its genetic limitations, has been extremely helpful in characterising the progression of brain degeneration. The novel Ts66Yah model represents an evolution of the Ts65Dn, with phenotypes only induced by trisomic HSA21 homologous genes, closer to human DS condition. In this study, we confirmed the behavioural features of Ts66Yah mice with improvement in the detection of spatial memory defects and also a new anxiety-related phenotype. The molecular characterisation of Ts66Yah demonstrated the aberrant regulation of redox balance, proteostasis, stress response, metabolic pathways, programmed cell death and synaptic plasticity. Intriguingly, the genotype-related alterations of those pathways occur early promoting the alteration of brain development and the onset of a condition of premature aging. Overall, data collected in Ts66Yah provide novel and consolidated insights, devoid of genome bias, concerning trisomy-driven processes that contribute to brain pathology in conjunction with aging. This, in turn, aids in bridging the existing gap in comprehending the intricate nature of DS phenotypes.

[1]  P. Cheah,et al.  Mitochondrial Dysfunction in Down Syndrome: From Pathology to Therapy , 2022, Neuroscience.

[2]  T. Haydar,et al.  Neurodevelopment in Down syndrome: Concordance in humans and models , 2022, Frontiers in Cellular Neuroscience.

[3]  F. Wiseman,et al.  Rodent Modeling of Alzheimer's Disease in Down Syndrome: In vivo and ex vivo Approaches , 2022, Frontiers in Neuroscience.

[4]  E. Fisher,et al.  Mouse models of aneuploidy to understand chromosome disorders , 2021, Mammalian genome : official journal of the International Mammalian Genome Society.

[5]  C. Martínez-Cué,et al.  Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials , 2020, Antioxidants.

[6]  P. Walter,et al.  The integrated stress response: From mechanism to disease , 2020, Science.

[7]  A. Tramutola,et al.  Proteostasis Failure in Neurodegenerative Diseases: Focus on Oxidative Stress , 2020, Oxidative medicine and cellular longevity.

[8]  Lucas C. Reineke,et al.  Activation of the ISR mediates the behavioral and neurophysiological abnormalities in Down syndrome , 2019, Science.

[9]  R. Nixon,et al.  mTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy , 2019, Cell Death & Disease.

[10]  M. Hagiwara,et al.  DYRK1A and cognition: A lifelong relationship , 2019, Pharmacology & therapeutics.

[11]  K. Yaffe,et al.  Prevalence of Aging, Dementia, and Multimorbidity in Older Adults With Down Syndrome , 2018, JAMA neurology.

[12]  Y. Hérault,et al.  Rodent models in Down syndrome research: impact and future opportunities , 2017, Disease Models & Mechanisms.

[13]  M. Hagiwara,et al.  Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice , 2017, Proceedings of the National Academy of Sciences.

[14]  A. Dhanasekaran,et al.  Mouse models of Down syndrome: gene content and consequences , 2016, Mammalian Genome.

[15]  Y. Hérault,et al.  DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome , 2016, Front. Behav. Neurosci..

[16]  I. Dimauro,et al.  A simple protocol for the subcellular fractionation of skeletal muscle cells and tissue , 2012, BMC Research Notes.

[17]  Yueming Ding,et al.  Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn , 2011, Mammalian Genome.

[18]  Y. Hérault,et al.  Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling down syndrome , 2011, Mammalian Genome.

[19]  O. Isacson,et al.  Abnormal APP, cholinergic and cognitive function in Ts65Dn Down's model mice , 2005, Experimental Neurology.

[20]  R. Bronson,et al.  A mouse model for Down syndrome exhibits learning and behaviour deficits , 1995, Nature Genetics.

[21]  Kazuhiro Ishii,et al.  [Down syndrome]. , 2003, Ryoikibetsu shokogun shirizu.

[22]  M. Davisson,et al.  Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome. , 1990, Progress in clinical and biological research.