The online version of this article (https://doi.org/10.1186/s12974-018-1273-7) contains supplementary material, which is available to authorized users.
Nina Weishaupt and Qingfan Liu contributed equally to this work.
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. 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.
The 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.
APP21 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.
The 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.
Additional file 1: Figure S1 Morris water maze swim speed. Average speed across learning trials is not statistically different between WT and TG rats at any time point. Figure S2 Open field activity. TG animals spent significantly less time ambulating in the arena during the 10 min test period than WT counterparts at 3 months of age (A). Likewise, WT animals exhibit significantly more rearing activity (B). At 19 months, TG animals still spent significantly less ambulating than WT rats (C). Graphs show mean ± SEM. One asterisk indicates p < 0.05, two asterisks indicate p < 0.01 (Mann–Whitney test), n values indicated within graph bars. Figure S3 Luxol fast blue histology. Photomicrographs of coronal rat brain sections stained with Luxol fast blue from 3 months (A), 15 months (B), and 19 months (C) WT and TG rats. Higher magnification insets are from the (i) corpus callosum and (ii) internal capsule. Quantification in the anterior corpus callosum (D), posterior corpus callosum (E), and internal capsule (F) showed no significant differences in myelin content between genotypes or age time points. Graphs show mean ± SEM, n values indicated within graph bars. (DOCX 8940 kb)12974_2018_1273_MOESM1_ESM.docx
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- APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts
Shawn Narain Whitehead
- BioMed Central