The Dp16 Mouse Model of Down Syndrome: Phenotypic Characterization and Assessment of the Pro-Cognitive Agent RIV5061
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Authors
Tresidder, Kaitlyn
Date
Type
thesis
Language
eng
Keyword
Alzheimer's disease , Down syndrome , Cognitive impairment , Mouse models , Preclinical
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Abstract
Although there are many factors which can influence the development of Alzheimer’s disease (AD), the greatest non-genetic and genetic risk factors are aging and Down syndrome (DS), respectively. The Aldh2-/- mouse model is an oxidative stress-based model of age-related cognitive impairment shown to possess behavioural deficits and pathological changes characteristic of both AD and vascular cognitive impairment. Specifically, Aldh2-/- mice have increased amyloid-beta (A-beta) levels in their cerebral microvessels (CMVs), suggestive of cerebral amyloid angiopathy (CAA). To further investigate this, we assessed levels of the A-beta-disposition-related proteins neprilysin and low-density lipoprotein receptor-related protein 1 in the CMVs of male Aldh2-/- mice relative to wild-type. We found no differences in protein expression, indicating that absolute levels of these proteins are unlikely to account for the observed CAA-like pathology in Aldh2-/- mice. Since DS is the greatest genetic risk factor for AD development, we hypothesized that mouse models of DS might provide a useful complement to existing mouse models of AD, especially for the evaluation of novel therapeutics. Therefore, we assessed the effect of the pro-cognitive agent 4-methyl-5-(2-(nitrooxy) ethyl) thiazol-3-ium maleate (RIV5061) on the behavioural, biochemical, electrophysiological, and morphological properties of the Dp(16)1Yey/+ (Dp16) mouse model of DS. RIV5061 has previously shown pro-cognitive and anti-inflammatory effects in several AD mouse models. We found that male and female Dp16 mice, over a broad age range (2–14 months), exhibited few AD-like phenotypic differences compared with their euploid counterparts. Furthermore, after a twelve-week course of treatment with RIV5061, pro-cognitive effects of RIV5061 were not observed in Dp16 mice, nor were there consistent changes in protein biomarkers, hippocampal CA1 dendritic spine density or hippocampal long-term potentiation. There was, however, an anti-inflammatory effect of RIV5061, as evidenced by reduced expression of the astrocytic marker glial fibrillary acidic protein, in male and female Dp16 and euploid mice. Therefore, with respect to the parameters assessed, we conclude that Dp16 mice are not a particularly representative model of AD, and thus may be of limited value for the assessment of novel AD therapeutics. Dp16 mice may still adequately model DS-AD, but this awaits a more complete assessment of the Dp16 phenotype.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.