Article

APP transgenic mice for modelling behavioral and psychological symptoms of dementia (BPSD)

Département de Psychologie, Faculté des Sciences, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France.
Neuroscience & Biobehavioral Reviews (Impact Factor: 8.8). 02/2012; 36(5):1357-75. DOI: 10.1016/j.neubiorev.2012.02.011
Source: PubMed

ABSTRACT

The discovery of gene mutations responsible for autosomal dominant Alzheimer's disease has enabled researchers to reproduce in transgenic mice several hallmarks of this disorder, notably Aβ accumulation, though in most cases without neurofibrillary tangles. Mice expressing mutated and wild-type APP as well as C-terminal fragments of APP exhibit variations in exploratory activity reminiscent of behavioural and psychological symptoms of Alzheimer dementia (BPSD). In particular, open-field, spontaneous alternation, and elevated plus-maze tasks as well as aggression are modified in several APP transgenic mice relative to non-transgenic controls. However, depending on the precise murine models, changes in open-field and elevated plus-maze exploration occur in either direction, either increased or decreased relative to controls. It remains to be determined which neurotransmitter changes are responsible for this variability, in particular with respect to GABA, 5HT, and dopamine.

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    • "rylated tau protein. A variety of different transgenic mouse models overexpressing human amyloid-precursor protein (APP) has been generated during the last 15 years, reflecting various aspects of human pathology [1] [2]. These models differ in the APP isoform that is expressed (mainly APP695, APP751, or APP770), the use of mutations (e.g., Swedish, London, Florida, Arctic, or others), and the promoter constructs used to drive either ubiquitous (e.g., prion protein promoter) or neuron-specific expression (e.g., Thy-1) (reviewed in [3]). "
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    ABSTRACT: According to the modified amyloid hypothesis, the key event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid β-peptides (Aβs) in plaques and cerebral blood vessels. Additionally to full-length peptides, a great diversity of N-truncated Aβ variants is derived from the larger amyloid-β protein precursor (AβPP). Vast evidence suggests that Aβ x-42 isoforms play an important role in triggering neurodegeneration due to their high abundance, amyloidogenic propensity and toxicity. Although N-truncated Aβ peptides and Aβ x-42 species appear to be the crucial players in AD etiology, the Aβ 2-x isoforms did not receive much attention yet. The present study is the first to show immunohistochemical evidence of Aβ 2-x in cases of AD and its distribution in AβPP/PS1KI and 5XFAD transgenic mouse models using a novel antibody pAB77 that has been developed using Aβ 2-14 as antigen. Positive plaques and congophilic amyloid angiopathy (CAA) were observed in AD cases and in both mouse models. While in AD cases, abundant CAA and less pronounced plaque pathology was evident, the two mouse models showed predominantly extracellular Aβ deposits and minor CAA staining. Western blotting and a capillary isoelectric focusing immunoassay demonstrated the high specificity of the antibody pAb77 against Aβ-variants starting with the N-terminal Alanine-2.
    No preview · Article · Oct 2015 · Journal of Alzheimer's disease: JAD
    • "rylated tau protein. A variety of different transgenic mouse models overexpressing human amyloid-precursor protein (APP) has been generated during the last 15 years, reflecting various aspects of human pathology [1] [2]. These models differ in the APP isoform that is expressed (mainly APP695, APP751, or APP770), the use of mutations (e.g., Swedish, London, Florida, Arctic, or others), and the promoter constructs used to drive either ubiquitous (e.g., prion protein promoter) or neuron-specific expression (e.g., Thy-1) (reviewed in [3]). "
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    ABSTRACT: In the present report, we extend previous findings in the 5XFAD mouse model with regard to a characterization of behavioral deficits and neuropathological alterations. We demonstrate that these mice develop a robust age-dependent motor phenotype and spatial reference memory deficits when bred to homozygosity, leading to a strongly reduced age of onset of behavioral symptoms. At postnatal day sixteen, abundant AβPP was detected in subiculum and cortical pyramidal neurons. From six weeks on, intraneuronal Aβ could be detected which was much more abundant in homozygous mice. The same gene-dosage effect was seen on memory and motor deficits. While at 2 months of age neither heterozygous nor homozygous 5XFAD mice show any neurological phenotype, at 5 months they were clearly evident. Interestingly, despite abundant motor deficiencies, homozygous 5XFAD mice were able to perform the acquisition training of the Morris water maze task with no difference in the swimming performance between the groups. Therefore the aggravated spatial memory and spatial reference memory deficits of the homozygous mice correlated with the elevated soluble and insoluble Aβ levels. Homozygous 5XFAD mice represent a model with several advantages in comparison to the heterozygous mice, developing amyloid pathology much more rapidly together with a neurological phenotype. These advantages allow reducing the number of animals for Alzheimer's disease research.
    No preview · Article · Feb 2015 · Journal of Alzheimer's disease: JAD
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    • "Unchanged anxiety levels assessed by EPM were described in transgenic mice lacking amyloid plaques (Moran et al., 1995; Lalonde et al., 2002; Lee et al., 2004; Boon et al., 2010) and in two models with Aβ plaques (Arendash et al., 2001; Le Cudennec et al., 2008; Blanchard et al., 2009). It is important to note that behavior in EPM was not assessed in any of the transgenic rat models of AD described so far (Do Carmo and Cuello, 2013) and that our results in Tg+/− rats, lacking extracellular Aβ deposition even at late stages, are in agreement with the concept that changes of EPM behavior appear only in transgenic models of AD with an extensive neuropathological phenotype (Savonenko et al., 2003; Lee et al., 2006; Lalonde et al., 2012). It is important to note that the levels of exploration of open arms seem to be low as compared to other reports (see Figures 3C,D). "
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    ABSTRACT: Intraneuronal accumulation of amyloid β (iAβ) has been linked to mild cognitive impairment that may precede Alzheimer's disease (AD) onset. This neuropathological trait was recently mimicked in a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat. The characterization of the behavioral phenotypes in this animal model could provide a baseline of efficacy for earlier therapeutic interventions. The aim of the present study was to undertake a longitudinal study of Aβ accumulation and a comprehensive behavioral evaluation of this transgenic rat model. We assessed exploratory activity, anxiety-related behaviors, recognition memory, working memory, spatial learning and reference memory at 3, 6, and 12 months of age. In parallel, we measured Aβ by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble Aβ peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant Aβ oligomers (~30 kDa) at 6 and 12 months, but not at 3 months. When compared to wild-type (WT), male Tg+/− rats exhibited a spatial reference memory deficit in the Morris Water Maze (MWM) as early as 3 months of age, which persisted at 6 and 12 months. In addition, Tg+/− rats displayed a working memory impairment in the Y-maze and higher anxiety levels in the Open Field (OF) at 6 and 12 months of age, but not at 3 months. Exploratory activity in the OF was similar to that of WT at all-time points. Spatial learning in the MWM and the recognition memory, as assessed by the Novel Object Recognition Test, were unimpaired at any time point. The data from the present study demonstrate that the hemizygous transgenic McGill-R-Thy1-APP rat has a wide array of behavioral and cognitive impairments from young adulthood to middle-age. The low Aβ burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in early AD.
    Full-text · Article · Sep 2014 · Frontiers in Behavioral Neuroscience
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