Animal models of Alzheimer's disease and frontotemporal dementia

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.