An update of animal models of Alzheimer disease with a reevaluation of plaque depositions

Abstract

Animal models of Alzheimer disease (AD) are used to study the mechanisms underlying AD pathogenesis, genetic interactions with genes of interest, and environmental risk factors that cause sporadic AD as well as to test the therapeutic effects of AD drug-candidates on neuropathology and cognitive function. To attain a comparative view on the AD models developed, representative AD lines were selected and summarized with respect to transgenic constructs and AD-related pathology. In addition, age-dependent plaque deposition data available in the literature for six representative AD models such as Tg2576, PDAPP, TgAPP23, Tg-APPswe/PS1dE9, 3xTg-AD, and 5XFAD mice were reevaluated using a photographic plaque reference scale method that was introduced recently. Tg2576, PDAPP, and TgAPP23 mice, which carry the amyloid precursor protein (APP) transgene, produced initially slow, but progressively accelerated plaque deposition as they aged, resulting in logistic plaque deposition. In contrast, Tg-APPswe/PS1dE9 and 3xTg-AD mice, which carry both APP and PS1 transgenes, developed abruptly accelerated plaque formation from the beginning, resulting in logarithmic plaque deposition. 5XFAD mice, which also carry both the APP and PS1 transgenes, developed a logarithmic deposition beginning at 2 months. This comparative analysis suggests that AD models may be classified into two distinct plaque deposition groups, and that early plaque models such as APPswe/PS1dE9, 3xTg-AD and 5XFAD might be useful to study the biochemical aspects of APP metabolism, whereas late plaque models such as Tg2576, PDAPP, and TgAPP23 might be useful to study more physiological and environmental aspects of AD pathogenesis, which occur on a longer time scale.

Keywords: APP and PS1 models; APP models; Alzheimer disease; comparison of plaque levels; plaque deposition.

Fig. 1

Gene, age and other environmental factors on the development of Alzheimer disease (AD). Age-dependent pathogenesis of AD is an important common factor in early-onset familial AD (FAD; carrying mutations at APP, PS1 or PS2), late-onset FAD (carrying ApoE4 allele), and sporadic AD. In all cases of AD, aging or age-related accumulation of undefined factors appears to trigger AD pathogenesis. Environmental risk factors may include besides aging, stress, gender (female), acid-forming food containing high dietary fat or total energy, dioxins, aluminum, lead, and viral infections.

Fig. 2

Temporal plaque deposition patterns in the brains of six representative AD models. (A) Examples of quantifying plaque deposition levels in the brain of Tg-APPswe/PS1dE9 mice using the six-scale photographic plaque reference panels [44]. (B) Age-dependent plaque deposition in the brains of Tg2576, PDAPP, TgAPP23, Tg-APPswe/PS1dE9, 3xTg-AD, and 5XFAD mice are plotted with age. Photomicrographs showing plaque deposition in the parietal cortices for each line were searched for in the literature and their plaque deposition levels were re-evaluated using the six-scale photographic plaque reference panels. Plaque deposition levels for each line was reassessed using both the Tg2676 panels and Tg-APPswe/PS1dE9 panels [44], and plaque scores were averaged [25, 27, 44, 45, 47, 55-61]. (C) Age-dependent plaque deposition was re-evaluated using the six-scale reference panels in the brains of Tg2576, PDAPP, TgAPP23, Tg-APPswe/PS1dE9, 3xTg-AD, and 5XFAD mice and were aligned over the month showing first plaque deposition. Rapid and abrupt plaque accumulation was evident in the AD models that carry both APP and PS1 transgenes compared to the lines that carried the APP transgene. (D) Plaque deposition levels in Tg-APPswe/PS1dE9, 3xTg-AD, and 5xFAD mice plotted over log values of time (loge[months]) produced new plaque deposition patterns that were similar in shape to the un-converted plaque deposition profiles displayed by Tg2576, PDAPP, and TgAPP23 mice.