Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer’s disease

Abstract

Research into the underlying mechanisms of cognitive dysfunction in Alzheimer's disease (AD) has relied traditionally on tasks such as the water maze which evaluate spatial learning and memory. Since non-spatial forms of memory are also disrupted by AD, it is critical to establish other paradigms capable of investigating these deficits. Utilizing a non-spatial learning task, acquisition of conditioned taste aversion (CTA) was evaluated in a mouse model of AD. This line of transgenic mice encode a mutated allele of the human amyloid precursor protein (APP) and presenilin 1 (PS1) genes and exhibit extensive amyloid plaque deposition in the brain by 6-7 mo of age. Compared to wildtype mice, 10-17 month old APP/PS1 mice failed to acquire CTA to saccharin. Mice that only possessed one of the two mutations were able to acquire CTA to the saccharin. In 2-5 month old APP/PS1 mice acquisition of CTA was disrupted despite the lack of extensive plaque deposition. However, further analysis indicated a potential gender difference in both the CTA deficit and onset of plaque deposition with females showing greater conditioned aversion.Alzheimer's disease (AD) is one of the most prominent neurodegenerative disorders associated with aging. The hallmark symptom of AD is impaired learning and memory function that progresses from mild to severe. AD is characterized pathologically by extra-cellular deposition of beta-amyloid (Aβ) plaques and intra-cellular neurofibrillar tangles consisting of aggregrates of hyperphosphorylated protein tau (Selkoe, 1989, Mandelkow andMandelkow, 1998). The pathology is first observed in the hippocampal and cortical regions and has been shown to be correlated with deficits in learning and memory , although this linkage remains controversial (Morgan, 2003).Over the past decade the use of mice expressing human familial mutations of AD has provided insight into the relationship between the pathological mechanisms and memory impairments (Ashe, 2001). Mice expressing mutations in amyloid precursor protein (APP), presenilin-1 (PS1), presenilin-2 (PS2), tau or apolipoprotein (apoE) have been generated to model various behavioral physiological, pathological and biochemical aspects of AD (Corder et al., 1998, Ashe, 2000, Lewis et al., 2001, Gordon et al., 2002, Hwang et al., 2002, Jolas et al., 2002, Teter et al., 2002. The mice developed thus far to investigate the pathology and learning and memory associated deficits in AD do not include a mouse that possesses all of the 1 Correspondence: Dr. Paul J. Pistell, Nutritional Neuroscience and Aging Laboratory, Pennington Biomedical Research Center, 6400 Perkins Rd., Baton Rouge, Louisiana 70808, Tel: 225/763-2739, Fax: 225/763-0261, Email:Paul.Pistell@pbrc.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is pub...

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…APP/PS1 transgenic mice expressing mutant human APP and PS1 genes are a useful research tool to study Aβ-related pathogenesis. There are several studies characterizing cognitive as well as noncognitive abnormality in APP/PS1 mice at 15-24 months of age (Morgan et al 2000;Arendash et al 2001;Sadowski et al 2004;Wilcock et al 2004;Hooijmans et al 2007;Minkeviciene et al 2008;Pistell et al 2008;Mei et al 2010;Ke et al 2011;Gengler et al 2012;Manczak and Reddy 2012;Wang et al 2012;Duffy and Hölscher 2013;Do et al 2014;Huang et al 2015;Janus et al 2015;Sahlholm et al 2015;Yousefi et al 2015) (A detailed summary is available in Table 2). However, the majority of experiments utilize young or adult APP/PS1 mice, which does not replicate typical hallmarks of AD, such as severe hippocampal atrophy and extensive neuronal loss (Bales 2012;Bilkei-Gorzo 2014).…”

Deficits in object-in-place but not relative recency performance in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: Implications for object recognition

“…Interestingly, deficits in taste aversion learning -in which ingestion of a flavoured liquid is followed some time later with illness -have been reported in 2-5 month old APPswe/PS1dE9 mice [18,61].…”

“…In this particular mouse line, some findings 4 are consistent with the view that the degree of cognitive impairment is related to the level of plaque deposition [14]; but other work has cast doubt on this suggestion. First, cognitive deficits have been observed before plaque deposition in these animals [16,17,18]. This suggests that Aβ deposition is unrelated to cognitive decline, a conclusion supported by the fact that spatial learning deficits in older mice are correlated not with plaque load but with levels of soluble amyloid [19].…”

Involvement of cyclin-dependent kinase-like 2 in cognitive function required for contextual and spatial learning in mice

“…A strong aversive response can be elicited in mice by paired administration of saccharin flavor and a malaise-inducing intraperitoneal injection of LiCl. Because there is no apparent sex difference in the acquisition of CTA in experimental rodents (Dalla and Shors, 2009; Pistell et al, 2008), we evaluated CTA with data from male and female animals. There were no differences in the basal level of water or saccharin consumption before CTA between Cdkl2 +/+ and Cdkl2 LacZ/LacZ mice; water consumption in a day during training days, Cdkl2 +/+ males; 5.19 ± 0.50 ml vs. Cdkl2 LacZ/LacZ males; 5.09 ± 0.34 ml, Cdkl2 +/+ females; 4.72 ± 0.39 ml vs. Cdkl2 LacZ/LacZ females; 4.96 ± 0.48 ml, saccharin consumption for 20 min on conditioning day, Cdkl2 +/+ males; 1.03 ± 0.11 ml vs. Cdkl2 LacZ/LacZ males; 1.22 ± 0.07 ml, Cdkl2 +/+ females; 0.88 ± 0.06 ml vs. Cdkl2 LacZ/LacZ females; 0.92 ± 0.08 ml, and water consumption for 24 h on resting day, Cdkl2 +/+ males; 5.96 ± 0.35 ml vs. Cdkl2 LacZ/LacZ males; 4.94 ± 0.52 ml, Cdkl2 +/+ females; 4.92 ± 0.32 ml vs. Cdkl2 LacZ/LacZ females; 4.99 ± 0.64 ml).…”