AD = Alzheimer’s disease CBD = corticobasal degeneration FTDP-17 = frontotemporal dementia and Parkinsonism linked to chromosome 17 PiD = Pick’s disease PSP = progressive supranuclear palsy. Interaction model illustrating the potential of human wild-type and mutant tau transgenic animal models. In addition, these models have also been used to develop novel therapeutic strategies ( 55). This has been followed by validation in tissues from patients with AD and FTD. As outlined below, they have been used to identify pathomechanisms, disease modifiers and differentially expressed genes and proteins. Over the past decade, many tau transgenic animal models have been developed that reproduce aspects of AD and FTD ( Figure 1). So far, 39 different Tau mutations have been identified in over 100 families. In addition to FTD, Tau mutations can give rise to clinical syndromes that resemble PSP, CBD, PiD and progressive subcortical gliosis ( 16, 44, 86, 153). These findings established that dysfunction of tau can cause neurodegeneration and lead to dementia. In 1998, research into tau was spurred on by the identification of exonic and intronic mutations in the Tau gene in FTDP-17, a familial dementia related to AD ( 69, 119, 137). These pathogenic mutations account for less than 1% of AD cases ( 27). Instead, mutations have been identified in the amyloid precursor protein ( APP) gene, from which Aβ is derived by proteolytic cleavage, and in the presenilin-1 ( PS1) and presenilin-2 ( PS2) genes, both of which encode proteins involved in Aβ formation. Mutations in Tau have not been found in AD. In addition to phosphorylation, tau is subject to ubiquitination, nitration, truncation, prolyl isomerization, association with heparan sulphate proteoglycans, glycosylation, glycation and modification by advanced glycation end-products (AGEs) ( 20). This increases the pool of soluble tau and is thought to trigger the disintegration of microtubules ( 43). Phosphorylation decreases the binding of tau to microtubules. Under pathological conditions, tau becomes hyperphosphorylated, which means a higher degree of phosphorylation at physiological sites, as well as de novo phosphorylation at additional sites ( 15, 43).
Tau contains a particularly high content of serines and threonines, many of which are phosphorylated under physiological conditions ( 42). Moreover, in some diseases, tau also forms aggregates in glial cells and these can outnumber neurons with aggregates ( 48). Tau is expressed predominantly in neurons and at lower levels in astrocytes and oligodendrocytes ( 143). In the absence of plaques, tau inclusions are abundant in a range of neurodegenerative diseases, which include Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease, sporadic frontotemporal dementia (FTD) and the inherited FTD and Parkinsonism linked to chromosome 17 (FTDP-17) ( 48, 86). They are found in nerve cell bodies and apical dendrites as neurofibrillary tangles (NFTs), in distal dendrites as neuropil threads and in the abnormal neurites that are associated with some amyloid plaques (neuritic plaques). This review focuses on tau, a microtubule-associated protein (MAP) and the principal component of the neurofibrillary lesions ( 41). Histopathologically, the Alzheimer’s disease (AD) brain is characterized by abundant amyloid plaques, neurofibrillary lesions and the loss of nerve cells and synapses. Moreover, the existence of a number of neurodegenerative diseases with tau pathology in the absence of extracellular deposits underscores the relevance of research on tau. While tau has received less attention than Aβ, it is rapidly acquiring a more prominent position and the emerging view is one of a synergistic action of Aβ and tau in Alzheimer’s disease. We discuss how the tau models have been used to unravel the pathophysiology of Alzheimer’s disease, to search for disease modifiers and to develop novel treatment strategies. They have been instrumental for dissecting the cross-talk between tau and the second hallmark lesion of Alzheimer’s disease, the Aβ peptide-containing amyloid plaque. Animal models, both in vertebrates and invertebrates, were significantly improved and refined as a result of the identification of pathogenic mutations in Tau in human cases of frontotemporal dementia. Since then, much has been learned about the role of tau in Alzheimer’s disease and related disorders. The first tau transgenic mouse model was established more than a decade ago.
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