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

ABSTRACT: Intraneuronal accumulation of amyloid ? (iA?) 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 A? 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 A? by ELISA, Western blots and semiquantitative immunohistochemistry in hippocampal samples. SDS-soluble A? peptide accumulated at low levels (~9 pg/mg) without differences among ages. However, Western blots showed SDS-resistant A? 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 A? burden and early emotional and cognitive deficits in this transgenic rat model supports its potential use for drug discovery purposes in early AD.

SUBMITTER: Galeano P

PROVIDER: S-EPMC4165352 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Galeano Pablo P Martino Adami Pamela V PV Do Carmo Sonia S Blanco Eduardo E Rotondaro Cecilia C Capani Francisco F Castaño Eduardo M EM Cuello A Claudio AC Morelli Laura L

Frontiers in behavioral neuroscience 20140916

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 ...[more]

PMID: 25278855

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Project description:OBJECTIVE The double transgenic mouse model (APPswe/PS1dE9) of Alzheimer's disease (AD) has been widely used in experimental studies. β-Amyloid (Aβ) peptide is excessively produced in AD mouse brain, which affects synaptic function and the development of central nervous system. However, little has been reported on characterization of this model. The present study aimed to characterize this mouse AD model and its wild-type counterparts by biochemical and functional approaches. METHODS Blood samples were collected from the transgenic and the wild-type mice, and radial arm water maze behavioral test was conducted at the ages of 6 and 12 months. The mice were sacrificed at 12-month age. One hemisphere of the brain was frozen-sectioned for immunohistochemistry and the other hemisphere was dissected into 7 regions. The levels of Aβ1-40, Aβ1-42 and 8-hydroxydeoxyguanosine (8-OHdG) in blood or/and brain samples were analyzed by ELISA. Secretase activities in brain regions were analyzed by in vitro assays. RESULTS The pre-mature death rate of transgenic mice was approximately 35% before 6-month age, and high levels of Aβ(1-40) and Aβ(1-42) were detected in these dead mice brains with a ratio of 1:10. The level of blood-borne Aβ at 6-month age was similar with that at 12-month age. Besides, Aβ(1-40) level in the blood was significantly higher than Aβ(1-42) level at the ages of 6 and 12 months (ratio 2.37:1). In contrast, the level of Aβ(1-42) in the brain (160.6 ng/mg protein) was higher than that of Aβ(1-40) (74 ng/mg protein) (ratio 2.17:1). In addition, the levels of Aβ(1-40) and Aβ(1-42) varied markedly among different brain regions. Aβ(1-42) level was significantly higher than Aβ(1-40) level in cerebellum, frontal and posterior cortex, and hippocampus. Secretase activity assays did not reveal major differences among different brain regions or between wild-type and transgenic mice, suggesting that the transgene PS1 did not lead to higher γ-secretase activity but was more efficient in producing Aβ(1-42) peptides. 8-OHdG, the biomarker of DNA oxidative damage, showed a trend of increase in the blood of transgenic mice, but with no significant difference, as compared with the wild-type mice. Behavioral tests showed that transgenic mice had significant memory deficits at 6-month age compared to wild-type controls, and the deficits were exacerbated at 12-month age with more errors. CONCLUSION These results suggest that this mouse model mimics the early-onset human AD and may represent full-blown disease at as early as 6-month age for experimental studies.

Project description:Incipient Alzheimer's Disease (AD) is characterized by a slow onset of clinical symptoms, with pathological brain changes starting several years earlier. Consequently, it is necessary to first understand and differentiate age-related changes in brain regions in the absence of disease, and then to support early and accurate AD diagnosis. However, there is poor understanding of the initial stage of AD; seemingly healthy elderly brains lose matter in regions related to AD, but similar changes can also be found in non-demented subjects having mild cognitive impairment (MCI). By using a Linear Mixed Effects approach, we modelled the change of 166 Magnetic Resonance Imaging (MRI)-based biomarkers available at a 5-year follow up on healthy elderly control (HC, n = 46) subjects. We hypothesized that, by identifying their significant variant (vr) and quasi-variant (qvr) brain regions over time, it would be possible to obtain an age-based null model, which would characterize their normal atrophy and growth patterns as well as the correlation between these two regions. By using the null model on those subjects who had been clinically diagnosed as HC (n = 161), MCI (n = 209) and AD (n = 331), normal age-related changes were estimated and deviation scores (residuals) from the observed MRI-based biomarkers were computed. Subject classification, as well as the early prediction of conversion to MCI and AD, were addressed through residual-based Support Vector Machines (SVM) modelling. We found reductions in most cortical volumes and thicknesses (with evident gender differences) as well as in sub-cortical regions, including greater atrophy in the hippocampus. The average accuracies (ACC) recorded for men and women were: AD-HC: 94.11%, MCI-HC: 83.77% and MCI converted to AD (cAD)-MCI non-converter (sMCI): 76.72%. Likewise, as compared to standard clinical diagnosis methods, SVM classifiers predicted the conversion of cAD to be 1.9 years earlier for females (ACC:72.5%) and 1.4 years earlier for males (ACC:69.0%).

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

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

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