Behavioural phenotype of APPC100.V717F transgenic mice over-expressing a mutant Aβ-bearing fragment is associated with reduced NMDA receptor density

Boon, Wah Chin; Buuse, Maarten van den; Wegener, Nico; Martin, Sally; Chua, H.; Bush, Ashley I.; Masters, Colin L.; Adlard, Paul A.; Li, Qiao‐Xin

doi:10.1016/j.bbr.2010.01.013

Cited by 13 publications

(9 citation statements)

References 55 publications

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“…Moreover, since hyperactivity has been reported prior to Aβ plaque formation in models cited above, it is not surprising to find the same phenotype exhibited in two models which never develop Aβ plaques at all, namely APP /C100/IND and APP /C100/WT (Boon et al, 2010). …”

Section: Exploratory Activity In Alzheimer Micementioning

confidence: 69%

“…However, no such impairment was found in two others carrying Aβ plaques: APP 695 SWE/IND (Hyde et al, 2005) and APP 695 SWE/co+ PS1 /ΔE9 (Bonardi et al, 2011; Frye and Walf, 2008; Harrison et al, 2009a,b; Lalonde et al, 2004, 2005). These negative results appear despite findings of alternation deficits in four models without Aβ plaques, namely APP 751 WT (Moran et al, 1995), APP /C100/IND (Boon et al, 2010), App 695 WT (Hsiao et al, 1995), and APP 695 TRI myc (Hsiao et al, 1995), though not in three others: APP 695 SWEch (Savonenko et al, 2003), APP /C100/WT (Boon et al, 2010), and APP /C99 (Lalonde et al, 2002a). …”

Section: Exploratory Activity In Alzheimer Micementioning

confidence: 90%

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

Lalonde

Fukuchi

Strazielle

2012

Neuroscience & Biobehavioral Reviews

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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 behavioral and psychological symptoms of Alzeimer 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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Section: Exploratory Activity In Alzheimer Micementioning

confidence: 69%

Section: Exploratory Activity In Alzheimer Micementioning

confidence: 90%

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

Lalonde

Fukuchi

Strazielle

2012

Neuroscience & Biobehavioral Reviews

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“…We were unable to detect differences in anxiety-related behaviors between Tg +/− and WT rats in the EPM test in the present study. 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).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease

Galeano

Adami

Carmo

et al. 2014

Front. Behav. Neurosci.

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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.

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“…Plasma Aβ levels do not correlate with brain deposits [31] although deposits can be found in muscle with associated myopathy when the cDNA is driven by a chimeric cytomegalovirus enhancer and chick β-actin promoter instead of the brain-specific promoters [55, 127], suggesting that differential promoter usage may contribute to the varied phenotypes observed. Not surprisingly, adding a familial AD (FAD) mutation (V717F) in the CT100 construct gave rise to phenotypes more severe than mice expressing wild-type CT100 [18, 72]. These mice have reduced expression of NMDA receptor subunits, disrupted axonal morphology, increased number of TUNEL-positive cells in CA1, as well as increased hyperactivity at a young age and cognitive deficits [18].…”

Section: App Proteolytic Fragmentsmentioning

confidence: 99%

“…Not surprisingly, adding a familial AD (FAD) mutation (V717F) in the CT100 construct gave rise to phenotypes more severe than mice expressing wild-type CT100 [18, 72]. These mice have reduced expression of NMDA receptor subunits, disrupted axonal morphology, increased number of TUNEL-positive cells in CA1, as well as increased hyperactivity at a young age and cognitive deficits [18]. …”

Section: App Proteolytic Fragmentsmentioning

confidence: 99%

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

2014

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The amyloid precursor protein (APP) has occupied a central position in Alzheimer’s disease (AD) pathophysiology, in large part due to the seminal role of amyloid-β peptide (Aβ), a proteolytic fragment derived from APP. Although the contribution of Aβ to AD pathogenesis is accepted by many in the research community, recent studies have unveiled a more complicated picture of APP’s involvement in neurodegeneration in that other APP-derived fragments have been shown to exert pathological influences on neuronal function. However, not all APP-derived peptides are neurotoxic, and some even harbor neuroprotective effects. In this review, we will explore this complex picture by first discussing the pleiotropic effects of the major APP-derived peptides cleaved by multiple proteases, including soluble APP peptides (sAPPα, sAPPβ), various C- and N-terminal fragments, p3, and APP intracellular domain fragments. In addition, we will highlight two interesting sequences within APP that likely contribute to this duality in APP function. First, it has been found that caspase-mediated cleavage of APP in the cytosolic region may release a cytotoxic peptide, C31, which plays a role in synapse loss and neuronal death. Second, recent studies have implicated the –YENPTY– motif in the cytoplasmic region as a domain that modulates several APP activities through phosphorylation and dephosphorylation of the first tyrosine residue. Thus, this review summarizes the current understanding of various APP proteolytic products and the interplay among them to gain deeper insights into the possible mechanisms underlying neurodegeneration and AD pathophysiology.

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Behavioural phenotype of APPC100.V717F transgenic mice over-expressing a mutant Aβ-bearing fragment is associated with reduced NMDA receptor density

Cited by 13 publications

References 55 publications

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

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

Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease

The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes

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