Abstract
Alzheimer's disease is a progressive neurodegenerative disease that manifests as memory loss, cognitive dysfunction, and dementia. Animal models of Alzheimer's disease have been instrumental in understanding the underlying pathological mechanism and in evaluation of potential therapies. The triple transgenic (3×Tg) mouse model of AD is unique because it recapitulates both pathologic hallmarks of Alzheimer's disease - amyloid plaques and neurofibrillary tangles. The earliest cognitive deficits in this model have been shown at 6-m of age by most groups, necessitating aging of the mice to this age before initiating evaluation of the cognitive effects of therapies. To assess cognitive deficits in the 3×Tg mice, originally we employed a typical Barnes maze protocol of 15 training trials, but found no significant deficits in aged mice. Therefore, we shortened the protocol to include only 5 training trials to increase difficulty. We found cognitive deficits using this protocol using mainly measures from the probe day, rather than the training trials. This also decreased the effort involved with data analysis. We compared 3×Tg and wild-type mice at 4-m- and 15-m of age using both the original, long training, and the short training paradigms. We found that differences in learning between 3×Tg and wild-type mice disappeared after the 4th training trial. Measures of learning and memory on the probe day showed significant differences between 3×Tg and wild-type mice following the short, 5-training trial protocol but not the long, 15-training trial protocol. Importantly, we detected cognitive dysfunction already at 4-m of age in 3×Tg mice using the short Barnes-maze protocol. The ability to test learning and memory in 4-m old 3×Tg mice using a shortened Barnes maze protocol offers considerable time and cost savings and provides support for the utilization of this model at pre-pathology stages for therapeutic studies.
Highlights
Learning and memory deficits are relatively difficult to assess compared to other phenotypes, and there is an abundance of papers describing cognitive deficit assessment in models of AD, replicating these studies de novo based on the literature often is challenging
Based on our extensive literature search on the Barnes maze in AD models, we developed a 15-training trial protocol and following its execution, found that either our 36Tg mice did not have cognitive deficits compared to WT mice or the test was not sensitive enough to detect the deficits
Our analysis of the training day latencies in the initial longtraining paradigm, which included 15 training trials showed that consistent differences in latency between the WT and 36Tg groups existed only in the first 4 trials followed by stochastic values in the remaining trials, especially for the 36Tg group (Fig. 2A)
Summary
Learning and memory deficits are relatively difficult to assess compared to other phenotypes, and there is an abundance of papers describing cognitive deficit assessment in models of AD, replicating these studies de novo based on the literature often is challenging. The age by which particular animal models of AD display cognitive deficits varies substantially, among models, and in a particular model tested by different groups [2,4,5,6,7]. In addition to these challenges, assessing cognitive deficits in animal models is quite costly. If the mice need to be aged to an older age, as in the case of the 36Tg model [8], which according to the literature often is used at 10-m of age or older to show convincing deficits [9,10,11] compared to control wild-type (WT) animals, the costs increase substantially
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