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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that frequently begins with memory complaints progressing to a severe deterioration of multiple memory systems (Eustache et al, 2006)
Some of the classical neuropathological changes in AD are the presence of amyloid β (Aβ) deposits and neurofibrillary tangles which initiate in the entorhinal cortex and hippocampus, and spread to the medial temporal lobe (Scahill et al, 2002)
SDS-resistant Aβ oligomers appeared in hippocampal homogenates of 6 and 12 months old Tg+/− rats, but not in 3 months old Tg+/− rats
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that frequently begins with memory complaints progressing to a severe deterioration of multiple memory systems (Eustache et al, 2006). Some of the classical neuropathological changes in AD are the presence of amyloid β (Aβ) deposits and neurofibrillary tangles which initiate in the entorhinal cortex and hippocampus, and spread to the medial temporal lobe (Scahill et al, 2002) This progression of neuropathology leads to episodic and semantic memory deficits that can be detected at early stages of the disease (Bondi et al, 1999, 2008; Collie and Maruff, 2000; Schmitt et al, 2000; Smith et al, 2007). Aging is the predominant risk factor for AD and there is biochemical evidence supporting that the disease has an extensive preclinical phase (Sperling et al, 2011; Bateman et al, 2012). The relevance of the early stage of AD is further supported
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