Spatial memory deficits in a mouse model of late-onset Alzheimer’s disease are caused by zinc supplementation and correlate with amyloid-beta levels

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dc.contributor.authorFlinn, Jane M.
dc.contributor.authorBozzelli, P. Lorenzo
dc.contributor.authorAdlard, Paul A.
dc.contributor.authorRailey, Angela M.
dc.date.accessioned2015-10-12T17:21:54Z
dc.date.available2015-10-12T17:21:54Z
dc.date.issued2014-10-22
dc.description.abstractMuch of the research in Alzheimer’s disease (AD) that uses mouse models focuses on the early-onset form of the disease, which accounts for less than 5% of cases. In contrast, this study used a late-onset AD model to examine the interaction between increased dietary zinc (Zn) and the apolipoprotein E (ApoE) gene. ApoE ε4 is overrepresented in late-onset AD and enhances Zn binding to amyloid-β (Aβ). This study sought to determine if elevated dietary Zn would impair spatial memory in CRND8 mice (CRND8), as well as mice who carry both the mutated human amyloid precursor protein (APP) and ApoE ε4 genes (CRND8/E4). Mice were provided with either lab tap water or water enhanced with 10 ppm Zn (ZnCO3) for 4 months. At 6 months of age, spatial memory was measured by the Barnes maze. CRND8 mice exhibited significant memory deficits compared to WT mice, as shown by an increased latency to reach the escape box. For the CRND8/E4, but not the CRND8 mice, those given Zn water made significantly more errors than those on lab water. During the probe trial for the WT group, those on Zn water spent significantly less time in the target quadrant than those on lab water. These data suggest that increased dietary Zn can significantly impair spatial memory in CRND8/E4. WT mice given Zn water were also impaired on the 24-h probe trial when compared to lab water WTs. Within the CRND8/E4 group only, levels of soluble Aβ were significantly correlated with average primary latencies. Within the Zn-treated CRND8/E4 group, there was a significant correlation between insoluble Aβ and average primary errors. Levels of the zinc transporter 3, ZnT3, were negatively correlated with soluble Aβ (p < 0.01). These findings are particularly relevant because increased intake of dietary supplements, such as Zn, are common in the elderly—a population already at risk for AD. Given the effects observed in the CRND8/E4 mice, ApoE status should be taken into consideration when evaluating the efficacy of therapies targeting metals.
dc.description.sponsorshipThis research was funded in part by a Sigma Xi GIAR and an APA dissertation research award to Angela M. Railey. Paul Anthony Adlard is supported by the NHMRC and ARC. In addition, the Florey Institute of Neuroscience and Mental Health acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant. Publication of this article was funded in part by the George Mason University Libraries Open Access Fund.
dc.identifier.citationFlinn JM, Bozzelli PL, Adlard PA and Railey AM (2014) Spatial memory deficits in a mouse model of late-onset Alzheimer’s disease are caused by zinc supplementation and correlate with amyloid-beta levels. Front. Aging Neurosci. 6:174. doi: 10.3389/fnagi.2014.00174
dc.identifier.doihttp://dx.doi.org/10.3389/fnagi.2014.00174
dc.identifier.urihttps://hdl.handle.net/1920/9937
dc.language.isoen_US
dc.publisherFrontiers Media
dc.rightsAttribution 3.0 United States
dc.rights.urihttps://creativecommons.org/licenses/by/3.0/us/
dc.subjectApolipoprotein E,
dc.subjectHAPP
dc.subjectCRND8
dc.subjectTransgenic mice
dc.subjectBarnes maze
dc.subjectMetals
dc.subjectZnT3
dc.subjectCopper
dc.titleSpatial memory deficits in a mouse model of late-onset Alzheimer’s disease are caused by zinc supplementation and correlate with amyloid-beta levels
dc.typeArticle

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