Practical considerations for choosing a mouse model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized by the triad of β-amyloid plaques, neurofibrillary tangles, and neurodegeneration. Genetic mutations and risk factors have been identified that are either causal or modify the disease progression. These genetic and pathological features serve as basis for the creation and validation of mouse models of AD. Efforts made in the past quarter-century have produced over 100 genetically engineered mouse lines that recapitulate some aspects of AD clinicopathology. These models have been valuable resources for understanding genetic interactions that contribute to disease and cellular reactions that are engaged in response. Here we focus on mouse models that have been widely used stalwarts of the field or that are recently developed bellwethers of the future. Rather than providing a summary of each model, we endeavor to compare and contrast the genetic approaches employed and to discuss their respective advantages and limitations. We offer a critical account of the variables which may contribute to inconsistent findings and the factors that should be considered when choosing a model and interpreting the results. We hope to present an insightful review of current AD mouse models and to provide a practical guide for selecting models best matched to the experimental question at hand.

Keywords: APP; Amyloid precursor protein; ApoE; Apolipoprotein E; Aβ; Knock-in; Knockout; MAPT; TREM2; Tau; Transgenic mouse.

Fig. 1

Diagram of APP illustrating nine FAD mutations that have been incorporated into mouse models. The Aβ domain is highlighted in red, with the β- and γ-cleavage sites identified at residues 671 and 714, respectively, using the numbering convention for full-length 770 amino acid protein. The amino acid sequence of Aβ is outlined in red, with the positions of several commonly used FAD mutations and their amino acid substitutions shown (in bold) alongside the geographic name identifying each variant. Italic residues indicate the three sites at which the Aβ sequence diverges between human and mouse (human is shown). Swe, Swedish; Arc, Arctic; Aus, Austrian; Lon, London; Ind, Indiana; Ibe, Iberian; Flo, Florida