Animal models for Alzheimer's disease and frontotemporal dementia: a perspective

Abstract

In dementia research, animal models have become indispensable tools. They not only model aspects of the human condition, but also simulate processes that occur in humans and hence provide insight into how disease is initiated and propagated. The present review discusses two prominent human neurodegenerative disorders, Alzheimer's disease and frontotemporal dementia. It discusses what we would like to model in animals and highlights some of the more recent achievements using species as diverse as mice, fish, flies and worms. Advances in imaging and therapy are explored. We also discuss some anticipated new models and developments. These will reveal how key players in the pathogenesis of Alzheimer's disease and frontotemporal dementia, such as the peptide Aβ (amyloid β) and the protein tau, cause neuronal dysfunction and eventually, neuronal demise. Understanding these processes fully will lead to early diagnosis and therapy.

Figure 1. Aspects of AD and FTD one would like to model in animals

Animal models have become indispensable in basic and biomedical research. They reproduce aspects of AD and FTD (A–D), but also allow for testing the many hypotheses that have been put forward to determine what exactly causes these diseases (E). In both AD and FTD, protein aggregation leads to lesions that can be visualized under the light microscope either by immunohistochemistry, by dyes such as thioflavin S, or by silver impregnation methods such as those developed by Gallyas and Bielschowsky, an aspect to be modelled (as indicated by the ‘M’) in animals (A). A second aspect is that of the spreading of the key histopathological hallmarks of AD, the Aβ plaques and the tau tangles (NFTs) that has led to the definition of the Braak stages (B). A third is the distinct clinical features such as memory impairment in AD or parkinsonism that characterizes a subset of FTD cases (C). The fourth is the distinct age of onset and disease duration that discriminates, e.g. carriers of mutations in the tau-encoding MAPT gene compared with those in the progranulin-encoding PGRN gene (D) based on data in (Cruts and Van Broeckhoven, 2008). The list of hypotheses in the field is led by the amyloid cascade hypothesis, but animal models provide support for all proposed hypotheses (E).

Figure 2. Transgenesis supports the amyloid cascade hypothesis in mice

Crossing P301L tau mutant JNPL3 mice with APP mutant Tg2576 mice causes a 7-fold increased NFT induction, but no increased Aβ pathology (A). Similarly, intracerebral (i.c.) injections of synthetic Aβ42 preparations cause a 5-fold induction of NFTs in P301L tau mutant pR5 mice (B). 3xtg-AD mice (P301L tau/APP^sw/PSEN^M146/− knockin), that combine an NFT and plaque pathology, show a prominent role for Aβ (C). A stereotaxic approach was used to inject extracts from Aβ plaque-forming APP23 mice [and not synthetic Aβ as in (B)] into P301L tau mutant JNPL3/B6 mice, again showing a role for Aβ in inducing a tau pathology (D).

Figure 3. Critical role for tau in Aβ toxicity

That tau is critical for Aβ-mediated toxicity, has been shown in primary neuronal cultures: wild-type (wt) neurons (A) degenerated when incubated with Aβ42, as did tau-transfected neurons (C). Primary neurons derived from tau knockout (KO) mice, however, were resistant to the toxic effects of Aβ (B). This has been translated in vivo. Most, if not all, APP mutant strains with a robust Aβ plaque pathology are characterized by premature death of unknown cause. This includes APP mutant J20 mice (D). By crossing these on to a hetero- or homo-zygous tau knockout background many clinical features could be ameliorated (E).

Figure 4. Modelling in animals and what has been achieved so far

Depending on how much weight we put on the different aspects of AD modelling (symbolized by the ‘M’) in animals the balance of ‘achievement’ will vary. The distribution is not meant to be taken at face value, but thought to provide an idea of which aspects of the human disease need further development. Protein aggregation has been very faithfully modelled in animals, as have aspects of behavioural impairment. Support has been provided for all hypotheses proposed for AD and FTD. Some insight has been achieved into the molecular mechanisms of how soluble tau and the different assembly states of Aβ cause and initiate cellular demise, but a real understanding is still lacking. The more we move to the right, the less has been authentically modelled. There are indeed aspects which, for obvious reasons, cannot be modelled in animals at all, such as the language variants of FTD.

Figure 5. Selective vulnerability examined in two mouse models with neuronal loss

Selective vulnerability characterizes two selected mouse strains, one characterized by memory impairment [rTg(tauP301L)₄₅₁₀ line] and the other, in addition, by parkinsonism (K369I tau mutant K3 strain). The rTg(tauP301L)₄₅₁₀ mice lose 60% of CA1 hippocampal pyramidal neurons by 5.5 months, and only 23% remain by 8.5 months. In the K3 mice, loss of TH neurons is also only partial, with 60% lost by 24 months of age. What protects a subset of morphologically indistinguishable neurons within the respective brain area from cell death while others degenerate?