With regard to ??-amyloid, similar to other commonly used models of AD such as the Tg2576 mouse and the 5xFAD mouse, in the APP/PS1 KI model the amyloid burden occurs prior to the onset of cognitive deficits [40-43]. Other potential therapeutic targets such as elevated levels of oxidative stress and neuroinflammation also occur before selleck kinase inhibitor the observable cognitive deficits in the APP/PS1 KI mouse model [12,14,17,44]. With respect to oxidative stress, the APP/PS1 KI mouse model is also considerably different from other models such as the Tg2576 and 3xTG-AD mice in the magnitude and temporal time course of oxidative stress [15,44-48]. Elevated levels of oxidative stress have been linked to the cognitive deficits seen in AD [49,50].

In a study of the APP/PS1 KI mice [18], NADPH oxidase (a marker of oxidative stress) was reported to increase with the age of the animal and correlate with increased ??-amyloid levels. Further, this same study reported that NADPH oxidase is correlated with APP/PS1 KI behavioral performance in the Stone T-maze, with lower levels of NADPH oxidase and slight deficits observable at 4 to 6 months of age and both becoming more pronounced by 16 to 19 months of age [18]. This provides an example of how the APP/PS1 KI mouse could be a useful model to test preclinical therapeutics targeted at reducing oxidative stress. AD is a very complex disease, with many interrelated mechanisms and pathologies occurring concomitantly. Although no animal model fully replicates the human disease, AD mouse models are useful to investigate different aspects of AD pathology and disease progression.

AD mouse models have been invaluable in advancing our understanding of disease mechanisms and in preclinical testing of potential therapeutics. Paramount to the selection of the appropriate model for evaluation of potential therapeutic interventions is demonstration that the desired relevant target for the preclinical therapeutic is present in the model at a therapeutically relevant time. For example, GSK-3 the APP/PS1 KI model used here is an ideal model for assessing the pathogenesis and effects of early oxidative stress or dysregulated neuroinflammation as we recently showed [17]. In contrast, the APP/PS1 KI model lacks AD-relevant tau pathology. This model would therefore be inappropriate to examine topics relating to the effect of microtubule-associated tau disruption in AD.

Instead, a model such as the 3xTG-AD mouse (or another relevant model showing tau pathology) should be selected instead. Similarly, if AD-related motor deficits [51] are the target of research interest, Volasertib mw selection of an appropriate model (Figure ?(Figure4)4) showing motor deficits such as the Tg2576 or 5xFAD mouse would be salient, whereas a model like the APP/PS1 KI model that does not develop motor deficits would not be useful.