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Background: Trisomy of human chromosome 21 (Hsa21) results in a constellation of features known as Down syndrome (DS), the most common genetic form of intellectual disability. Hsa21 is orthologous to three regions in the mouse genome on mouse chromosome 16 (Mmu16), Mmu17 and Mmu10. We investigated genotype-phenotype relationships by assessing the contribution of these three regions to memory function and age-dependent cognitive decline, using three mouse models of DS, Dp1Tyb, Dp(17)3Yey, Dp(10)2Yey, that carry an extra copy of the Hsa21-orthologues on Mmu16, Mmu17 and Mmu10, respectively. Hypothesis: Prior research on cognitive function in DS mouse models has largely focused on models with an extra copy of the Mmu16 region and relatively little is known about the effects of increased copy number on Mmu17 and Mmu10 on cognition and how this interacts with the effects of aging. As aging is is a critical contributor to cognitive and psychiatric changes in DS, we hypothesised that ageing would differentially impact memory function in Dp1Tyb, Dp(17)3Yey, and Dp(10)2Yey, models of DS. Methods: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Results: Young (12-13 months and old (18-20 months mice Dp1Tyb, Dp(17)3Yey and Dp(10)2Yey mice were tested on a battery of object recognition memory test that assessed object novelty detection, novel location detection and associative object-in place memory. Following behavioral testing, hippocampal and frontal cortical tissue was analysed for expression of glutamatergic receptor proteins using standard immunoblot techniques. Conclusion: Our results show that distinct Hsa21-orthologous regions contribute differentially to cognitive dysfunction in DS mouse models and that aging interacts with triplication of Hsa21-orthologous genes on Mmu10. [ABSTRACT FROM AUTHOR]

Author(s): Veronika Souslova [1]; Paolo Cesare [1]; Yanning Ding [1]; Armen N. Akopian [1]; Louise Stanfa [2]; Rie Suzuki [2]; Katherine Carpenter [2]; Anthony Dickenson [2]; Susan Boyce [3]; Ray [...]

Background: Age is the biggest risk factor for Alzheimer's disease (AD) but being female also increases risk with ∼63% of AD patients being female. This sex difference could partly be explained by menopause‐related oestrogen deficiencies during ageing. Oestrogen is neuroprotective and it is highly probable this deficiency after the menopause affects neuronal survival and contributes to the onset of AD. Oestrogen receptors are found in mitochondria and evidence suggests that the neuroprotective effect of oestrogen involves supporting mitochondrial function. The clear link between mitochondrial dysfunction and the pathophysiology of AD suggests a decrease in the beneficial effects of oestrogen on mitochondrial function after the menopause would have serious consequences. We hypothesise that alterations in oestrogen, due to ageing and the menopause, affect mitochondrial function and contribute to the increased susceptibility of women to AD. Method: Levels of mitochondrial proteins, dynamin‐related protein‐1 (DRP‐1), mitofusin‐1/2 (Mfn1/2), mitochondrial dynamin‐like GTPase (OPA1) and the electron transport chain (ETC) complexes 1‐5, were measured using immunoblotting in frontal cortical brain samples from young (20‐36), middle‐aged (40‐53) and old (64‐99) men and women with no history of dementia and in AD patients (Braak stage 5/6, 69‐92 age). Result: In female AD brains a significant decrease was observed in Mnf1 and DRP‐1 compared to age‐matched females and in OPA1 in male AD compared to old male brains. Mnf2 and ETC complex 3 (cytochrome reductase) were significantly increased in female AD compared to male AD brains. DRP‐1 was significantly decreased in old males compared to middle‐aged males, while ETC complex 2 (succinate dehydrogenase) was significantly increased in old females compared to young females. Conclusion: We demonstrate for the first time age, sex and disease differences in the expression of proteins involved in various aspects of mitochondrial function including fusion, fission and energy production. These changes could underlie previous findings showing a range of mitochondrial abnormalities in AD brains and support the 'mitochondrial cascade hypothesis' that mitochondrial dysfunction is the primary event causing β‐amyloid deposition, synaptic degeneration, and NFT formation (Swerdlow et al., J. Alz. Dis. 2010 20:Suppl 2, 265‐79.). Our findings could partly explain female vulnerability to AD development. [ABSTRACT FROM AUTHOR]