An Assessment of Strain- And Visual Pigmentation-related Differences in Neurocognitive And Neurobehavioral Outcomes in the transgenic Cohen’s Alzheimer’s Disease Rat Model

Abstract

The global population is predicted to face a substantial rise in cases of Alzheimer’s Disease (AD) by the year 2050. To this end, we are still far from developing clear and effective pre-clinical treatments for forestalling, recovering, and preventing AD symptoms and pathological traits associated with a positive diagnosis. Pre-clinical research is critical for early stage development of effective drugs for later clinical phase trials. However, effective drugs may be moved forward as false positives when proper behavioral experimental controls or comparisons are either overlooked or lacking in the pre-clinical stages. Thus, these missteps can often delay or inappropriately advance drug candidates lacking true efficacy at this pre-clinical stage. One such pre-clinical model uses the Cohen's Alzheimer's Disease (AD) rat model which has a genetic background in the Fischer 344 (F344) rat. Unfortunately, the F344 rat is an albino rat that is visually non-pigmented with rather poor visual acuity when compared to its visually pigmented counter-parts. This raises a critical issue, that when visually non-pigmented rat models are used for pre-clinical study, much caution should be exercised as they may have an artificially truncated or reduced cognitive capacity making them a less informative model for neurocognitive and neurobehavioral evaluations. In order to assess this issue we crossed the F344 AD rat model with a Long Evans (LE) visually pigmented rat model to produce a LE AD rat model. We then compared these rats’ behavioral performances on the Open Field to assess locomotor activity, the Elevated Plus Maze to assess anxiety-like behaviors, and the NeuwirthTM-Holeboard Test to assess fear/escape vs. cognitive/exploratory behaviors over 2 days. The data revealed that across all tests that the females for each strain had increase locomotor activity, anxiety-like behaviors, and fear/escape and cognitive/exploratory behaviors. When evaluating the strains, across all tests the F344 AD rats had a lower bandwidth/range for the capacity of their behavioral deficits to be observed when compared to the LE AD rats. Thus, our findings show that if a cognitive enhancing drug and/or anxiety-like drug were to be used to treat AD through these rats in the pre-clinical testing phase that the LE AD rats would prove to be a better model as they can show a greater range of deficits with a greater range for cognitive recovery.