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Review
. 2014 Apr 23:5:88.
doi: 10.3389/fgene.2014.00088. eCollection 2014.

Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

Scott J Webster  1 , Adam D Bachstetter  1 , Peter T Nelson  2 , Frederick A Schmitt  3 , Linda J Van Eldik  4
Affiliations
Review

Using mice to model Alzheimer's dementia: an overview of the clinical disease and the preclinical behavioral changes in 10 mouse models

Scott J Webster et al. Front Genet. .

Abstract

The goal of this review is to discuss how behavioral tests in mice relate to the pathological and neuropsychological features seen in human Alzheimer's disease (AD), and present a comprehensive analysis of the temporal progression of behavioral impairments in commonly used AD mouse models that contain mutations in amyloid precursor protein (APP). We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. Behavioral tests discussed include spatial memory tests [Morris water maze (MWM), radial arm water maze (RAWM), Barnes maze], associative learning tasks (passive avoidance, fear conditioning), alternation tasks (Y-Maze/T-Maze), recognition memory tasks (Novel Object Recognition), attentional tasks (3 and 5 choice serial reaction time), set-shifting tasks, and reversal learning tasks. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans. Finally, the temporal progression of both cognitive and non-cognitive deficits in 10 AD mouse models (PDAPP, TG2576, APP23, TgCRND8, J20, APP/PS1, TG2576 + PS1 (M146L), APP/PS1 KI, 5×FAD, and 3×Tg-AD) are discussed in detail. Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.

Keywords: 3×TG-AD mice; APP mice; APP/PS1 mice; Alzheimer's disease; behavior; cognition; mouse models; neuropsychological assessment.

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Figures

Figure 1
Figure 1
Overview of the progression of cognitive deficits in human AD and in mouse models of AD. (A) In the human disease, the earliest AD-related cognitive deficits present themselves as episodic memory impairment during the late preclinical phase of the disease (Backman et al., ; Twamley et al., ; Bondi et al., 2008). Semantic memory deficits are the next to develop (Tuokko et al., ; Storandt et al., 2006), followed by impairments in executive functioning (Bondi et al., 2008), attention (Bondi et al., 2008), and visuospatial memory (Twamley et al., 2006) near the beginning of the MCI phase of the disease. As MCI progresses, deficits in verbal recall (Kryscio et al., ; Bondi et al., 2008) develop and impairments in general cognition (Bondi et al., 2008) become apparent. As the patient transitions into AD, all cognitive domains become affected. (B) The development of cognitive deficits in APP mouse models of AD shows similar patterns of progression. Consistently, the earliest observable impairments are in spatial working memory (Webster et al., 2013), as assessed through the use of water maze based tasks. These impairments are generally followed temporally by impairments in associative learning and reference memory, as assessed by maze alternation (Lalonde et al., 2012) and fear conditioning tasks (Kobayashi and Chen, 2005). Deficits in recognition memory usually present later in the spectrum of cognitive impairment than deficits in other domains (Eriksen and Janus, ; Hall and Roberson, ; Webster et al., 2013).
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