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Animal models of Alzheimer's disease and frontotemporal dementia

Nature Reviews Neuroscience volume 9, pages 532–544 (2008)Cite this article

Key Points

  • Alzheimer's disease (AD) is the most common cause of dementia, comprising 50–70% of all cases. Frontotemporal dementia (FTD) is less common, but makes up 50% of dementia cases presenting before age 60. At present neither can be cured.

  • The AD brain is characterized by massive neuronal cell and synapse loss at specific sites, as well as β-amyloid (Aβ) plaques and tau-containing neurofibrillary lesions. The neurofibrillary lesions (such as neurofibrillary tangles) are also abundant in FTD, in which there is an absence of overt plaques.

  • In familial AD (FAD), autosomal dominant mutations have been identified in three genes: APP, presenilin 1 (PSEN1) and PSEN2. In FTD with parkinsonism linked to chromosome 17 (FTDP-17), mutations were identified in MAPT (which encodes tau), and in FTD with tau-negative lesions, mutations in progranulin (PGRN) have been reported.

  • Tau transgenic mouse models for FTD proved that mutations found in familial cases of FTD (FTDP-17) accelerate tau aggregation and cause nerve cell dysfunction and loss. Transgenic mice with an inducible tau expression showed that elevated levels of tau impair memory function but that NFTs are not sufficient to cause cognitive decline or neuronal death.

  • Combinatorial transgenic approaches have shown that Aβ can promote tau pathology but also that increased lethality and susceptibility to excitotoxicity of Aβ-producing transgenic mice can be prevented by breeding the APP transgene into a tau-deficient background. By genetically interfering with β- and γ-secretase activity, the role of key enzymes in APP processing, Aβ deposition and memory impairment has been established.

  • Invertebrate models, such as the nematode C aenorhabditis elegans and the fruitfly Drosophila melanogaster, have emerged as a powerful tool in AD and FTD research. In tau transgenic flies neurodegeneration can occur without NFT formation and is associated with the accumulation of filamentous actin-containing rods.

  • Transcriptomic and proteomic techniques are increasingly being applied to animal models of AD and FTD, and have allowed the identification of novel differentially regulated genes and proteins. Proteomic work in transgenic mice suggests that mitochondria are early targets of Aβ and tau aggregates.

  • Imaging techniques such as positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI) and multiphoton imaging are increasingly being used for the clinical diagnosis of AD and FTD. In mice, Aβ plaques can be labelled with the PET tracer 11C-labelled Pittsburgh Compound-B (PIB) that enters the brain quickly.

  • Among the therapeutic strategies that have emerged from transgenic animal work, are the active and passive vaccination trials targeting Aβ. In tau transgenic mice, injections of the microtubule-binding drug paclitaxel have been shown to effectively ameliorate motor impairment.

  • The role of diet in preventing AD, in particular when it contains anti-oxidants such as Ginkgo biloba or green tea extracts is gaining recognition. Caloric restriction is a means to reduce Aβ plaque numbers in transgenic mice.

Abstract

Insoluble protein aggregates have been linked to Alzheimer's disease (AD) and frontotemporal dementia (FTD). Recent work in transgenic mice has shed light on the role of these aggregates by identifying soluble oligomeric species that may interfere with essential cellular mechanisms at an early disease stage. This review summarizes what we have learned about the roles of these proteins from transgenic mice and invertebrate species such as flies and worms. Proteomic and transcriptomic analyses of tissue from these animal models have identified new molecules with crucial roles in disease. Moreover, transgenic animals have been instrumental in defining drug targets and designing novel therapeutic strategies. With advanced imaging techniques that can be used in both humans and mice an early, preclinical diagnosis of AD and FTD could be within reach.

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Figure 1: Reproducing plaques and NFTs in transgenic mice.
Figure 2: Behavioural tests used to assess memory functions in AD mouse models.
Figure 3: Sequence alignment of Aβ and tau from vertebrate and invertebrate species.
Figure 4: Application of functional genomics to AD mouse models.

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Acknowledgements

We apologize to those whose work has not been cited due to space limitations. J.G. is a Medical Foundation Fellow. This work has been supported by the University of Sydney, the National Health & Medical Research Council (NHMRC), the Australian Research Council (ARC), the New South Wales Government through the Ministry for Science and Medical Research (BioFirst Program), the Nerve Research Foundation, the Medical Foundation (University of Sydney) and the Judith Jane Mason & Harold Stannett Williams Memorial Foundation to J.G. and the ARC, NHMRC and Deutsche Forschungsgesellschaft (DFG) to L.M.I.

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  1. Alzheimer's & Parkinson's Disease Laboratory, Brain & Mind Research Institute, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia

    Jürgen Götz & Lars M. Ittner

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Correspondence to Jürgen Götz.

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Transgenic mouse models discussed in this review (PDF 129 kb)

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Glossary

Nucleus basalis of Meynert

A group of cholinergic nerve cells in the basal forebrain, with numerous projections to the cortex.

Disinhibition

A reduced capacity to control and coordinate the immediate impulsive response to a distinct situation.

Autosomal dominance

An inheritance pattern in which an abnormal copy of a gene from one parent gives rise to the trait, even though the copy inherited from the other parent is normal.

ER-associated degradation

(ERAD). Pathway which targets misfolded proteins from the endoplasmic reticulum for degradation by the proteasome.

Pre-tangle

A somatic accumulation of hyperphosphorylated tau without fibrillar deposition. Pre-tangles represent early stages of NFT formation.

Drosophila melanogaster

Often simply termed Drosophila, belongs to the family of fruit-flies and is widely used as a genetic model organism.

Hirano body

Intraneuronal, often rod-like aggregate of actin and associated proteins found in certain neurodegenerative disorders, such as Alzheimer's disease and Creutzfeldt-Jakob disease.

Rational mutagenesis

Targeted mutation of a gene of interest based on previous analysis (for example, sequence alignment or functional domains/motifs), often using site-directed mutagenesis.

Caenorhabditis elegans

A roundworm (nematode) that has become a major model organism for molecular and developmental biology.

Modifier screen

Screen in which random mutations are introduced into an organism with a pre-existing phenotype, using a mutagen such as N-ethyl-N-nitrosourea (ENU). Mutants that modify (enhance or suppress) the pre-existing phenotype are then isolated.

RNA interference

(RNAi). A method by which double-stranded RNA is used to cause rapid degradation of endogenous RNA thereby precluding translation. This provides a simple way of studying the effects of the absence of a gene product.

Forward genetic screen

A genetic analysis that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis

Suppressor screen

A system used to identify genes that, when overexpressed, lead to the suppression of a mutant phenotype.

Transcriptomics

Large-scale studies of the expression of genes at the mRNA level, typically carried out using microarray technology.

Proteomics

Large-scale studies of the proteome, which comprises all proteins produced by an organism or system. This might also include the analysis of protein function, structures and secondary modifications, using techniques such as mass-spectrometry.

Mass-spectrometric analysis

A technique used to identify and measure biological and chemical compounds. It involves ionization, followed by the use of a magnetic or electrical field. Applications include the identification of proteins and sequencing of oligosaccharides.

State 3 respiration

Active respiration after adding a limited amount of ADP. The rate after all the ADP has been phosphorylated to ATP is termed state 4 respiration.

Uncoupled respiration

Respiration upon adding a reagent such as oligomycin (complex V inhibitor) that uncouples from ATPase.

Positron emission tomography

(PET). In vivo imaging technique used for diagnostic examination that involves the acquisition of physiological images based on the detection of positrons, which are emitted from a radioactive substance previously administered to the patient.

Computed tomography

Imaging technique that exploits the differences in absorption of X-rays by different tissues to give high-contrast images of anatomical structures. Computed tomography has relatively poor soft-tissue contrast, so iodinated contrast agents, which perfuse different tissue types at different rates, are commonly used to delineate tumours.

Magnetic resonance imaging

A non-invasive method used to obtain images of living tissue. It uses radio-frequency pulses and magnetic field gradients; the principle of nuclear magnetic resonance is used to reconstruct images of tissue characteristics (for example, proton density or water diffusion parameters).

Multiphoton imaging

A non-invasive form of microscopy in which a fluorochrome that would normally be excited by a single photon is stimulated quasisimultaneously by several photons of lower energy. Under these conditions, fluorescence increases as a function of the square of the light intensity, and decreases approximately as the square of the distance from the focus. Because of this behaviour, only fluorochrome molecules near the plane of focus are excited, greatly reducing light scattering and photodamage.

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Götz, J., Ittner, L. Animal models of Alzheimer's disease and frontotemporal dementia. Nat Rev Neurosci 9, 532–544 (2008). https://doi.org/10.1038/nrn2420

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