Sporadic AD has been difficult to model in laboratory rodents, as they do not naturally develop hallmarks of AD, such as amyloid plaques and neurofibrillary tangles. This is emphasized by the fact that the expression of two APP mutations by APP21 transgenic rats, each of which will result in familial AD in humans, does not result in amyloid plaque formation in old APP21 transgenic rats [
12]. The expression of the APP transgene in these rats therefore does not induce what can be considered “rat AD,” instead, it merely renders these rats capable of developing AD-like pathology when challenged [
12,
13]. As demonstrated in the present study, these rats do, however, present with spontaneous cognitive deficits, especially executive function deficits such as working memory and strategy shift ability. This finding supports accumulating evidence that amyloid plaques themselves may not be a good indicator of disease severity, and that soluble forms of amyloid may indeed be more neurotoxic and clinically meaningful [
21]. It is interesting that the transgene by itself does not seem to produce a progressive deficit in spatial working memory or long-term memory, as measured here in the Morris water maze task over the course of 19 months. Strategy shift ability was only tested once at the end of the study, which does not allow any conclusions as to the development of this deficit over time. It should be noted that when interpreting behavioral test results, Fisher 344 wildtype rats are known to deteriorate cognitively in behavioral tests as they age, and we can only measure the effect of the transgene beyond the naturally occurring cognitive decline of Fisher 344 rats [
22‐
24]. Moreover, due to the longitudinal design of the present study, rats are repeatedly exposed to the Morris water maze test and may become familiar with it to the point where learning deficits may have been masked, thereby underestimating the cognitive deficit in the current design. Future investigations will have to clarify whether APP21 transgenic rats show impairment specific to the Water maze test, or whether other spatial tests, e.g., the Barnes maze, as well as non-spatial learning and memory tasks, such as the novel object recognition test, also precipitate a cognitive deficit in these rats. Additionally, robust tasks such as set-shifting tasks will allow for a better assessment of executive dysfunction in the APP21 rat.
In line with the naturally occurring aging process in Fisher 344 rats, both WT and TG rats showed a clear age-related progression of white matter inflammation as measured by the presence of OX-6 positive, activated microglia in the corpus callosum and in the internal capsule. Based on the assessments at 15 and 19 months of age, APP21 TG rats seem to develop this pathology earlier than WT rats, but plateau so that both genotypes demonstrate similar OX-6-positive microglia load at 19 months of age. The presence of significantly increased white matter inflammation in TG rats compared to WT rats at 15 months of age suggests that TG rats are developing histological pathology in line with a pre-dementia state in humans earlier or more readily than wildtype rats do. Combined with cognitive deficits, APP21 TG rats seem to present a unique model of pre-AD pathology. This offers a novel opportunity to study preventative strategies for dementia in a pre-clinical rat model capable of undergoing sophisticated behavioral tests [
10].
A limitation to this study is that only male rats were investigated. It is possible that sexual dimorphisms exist between males and females with respect to behavioral responses as this has been reported in the past [
25]. Future work could investigate any sexual dimorphisms in behavior and pathology in APP21 TG rats. Even so, the fact that APP21 TG rats are sensitive to developing more severe pathology when challenged, but only over the course of several months, also mirrors the clinical situation with regards to known non-genetic risk factors for dementia in middle age, such as smoking, stroke, and multiple concussions or traumatic brain injury [
26], which have to our knowledge not been tested in this model. All these features make the APP21 TG rat a unique model for studying risk factors for AD.