Abstract
BackgroundMost of the animal models commonly used for preclinical research into Alzheimer’s disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD-like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much-needed pre-clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age.MethodsThe open field test was used as a measure of activity; and the Morris water maze was used to assess learning, memory, and strategy shift. Neuronal loss and microglia activation were also assessed throughout the brain.ResultsAPP21 transgenic rats showed deficits in working memory from an early age, yet memory recall performance after 24 and 72 h was equal to that of wildtype rats and did not deteriorate with age. A deficit in strategy shift was observed at 19 months of age in APP21 transgenic rats compared to Fischer wildtype rats. Histologically, APP21 transgenic rats demonstrated accelerated white matter inflammation compared to wildtype rats, but interestingly no differences in neuron loss were observed.ConclusionsThe combined presence of white matter pathology and executive function deficits mirrored what is often found in patients with mild cognitive impairment or early dementia, and suggests that this rat model will be useful for translationally meaningful studies into the development and prevention of sporadic AD. The presence of widespread white matter inflammation as the only observed pathological correlate for cognitive deficits raises new questions as to the role of neuroinflammation in cognitive decline.
Highlights
Most of the animal models commonly used for preclinical research into Alzheimer’s disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease
transgenic rats (TG) rats take longer for spatial learning due to a working memory deficit All rats were given 16 acquisitions to learn the location of a submerged platform in the Morris water maze task
This was seen in a consistent difference in trial latencies between the genotypes in the first eight trials of each acquisition session (p = 0.0006, two-way ANOVA, Fig. 2a), while swim speeds were comparable between the two groups across learning trials (Additional file 1: Figure S1)
Summary
We use behavior and histology, to characterize the transgenic (APP21) rat model for its pre-clinical use in studying mild cognitive impairment (MCI) and the early-phase of sporadic AD. These transgenic rats were created on a Fisher 344 background and express the human amyloid precursor protein (APP) gene with both Swedish and Indiana mutations [11]. As reported previously, these rats do not develop histological hallmarks of AD spontaneously when aged up to 30 months [12]. APP21 rats may have unique potential for translationally meaningful research into risk factors and preventative approaches to non-familial forms of dementia [16]
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