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

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.

Fus1 KO Mouse As a Model of Oxidative Stress-Mediated Sporadic Alzheimer's Disease: Circadian Disruption and Long-Term Spatial and Olfactory Memory Impairments

“…The Open Field was based on Chen et al (2013) and Galeano et al (2014), and was used to assess spontaneous exploratory activity and anxiety-related behaviors (Hall, 1934). Anxiety and exploratory activities were evaluated by allowing mice to freely explore an open field arena for 15 min.…”

“…Spatial reference learning and memory were evaluated in a water maze adapted from that previously described by Morris (1984) and was based on Van Dam et al (2003), Javed et al (2011), Chen et al (2013) and Galeano et al (2014). …”

Animal models for Alzheimer’s disease: a focused review of transgenic rodent models and behavioral assessment methods

“…Considering that the importance of spatial learning and memory deficit in the criterion of AD, MWM has been applied in the judgement of many potential AD animal model. MWM was used to test the cognitive deficits of a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat [66]. The data revealed that this transgenic rat exhibited spatial memory deficit in the MWM as early as 3 months old, which persisted at 6 and 12 months old when compared to wild-type rats [66].…”

“…MWM was used to test the cognitive deficits of a novel animal model of AD, the hemizygous transgenic McGill-R-Thy1-APP (Tg+/−) rat [66]. The data revealed that this transgenic rat exhibited spatial memory deficit in the MWM as early as 3 months old, which persisted at 6 and 12 months old when compared to wild-type rats [66]. In addition, MWM was used to test different ages of B6C3-Tg (APPswe/PSEN1dE9) double-transgenic mice to provide the evidence as an AD model [67].…”

Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

“…Notwithstanding these evidences, the disease progression is not completely understood, partly due to the challenges in the identification of at-risk population and the time required to follow-up them from middle-age to the eventual advanced phase of AD. In this sense, animal models provide a helpful approach to evaluate the development of AD from early to advanced stages (Do Carmo and Cuello, 2013;Galeano et al, 2014;Leon et al, 2010;Sabbagh et al, 2013). AD is related with the presence and interplay of both amyloid plaques and neurofibrilary tangles and therefore animal model should replicate these two aspects to lead to successful and translational results (Drummond and Wisniewski, 2017).…”