A Decade of Tau Transgenic Animal Models and Beyond

Abstract

The first tau transgenic mouse model was established more than a decade ago. Since then, much has been learned about the role of tau in Alzheimer's disease and related disorders. 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. They have been instrumental for dissecting the cross-talk between tau and the second hallmark lesion of Alzheimer's disease, the Ab peptide-containing amyloid plaque. 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. While tau has received less attention than Ab, it is rapidly acquiring a more prominent position and the emerging view is one of a synergistic action of Ab and tau in Alzheimer's disease. 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.Brain Pathol 2007;17:91-103. INTRODUCTIONHistopathologically, the Alzheimer's disease (AD) brain is characterized by abundant amyloid plaques, neurofibrillary lesions and the loss of nerve cells and synapses. This review focuses on tau, a microtubule-associated protein (MAP) and the principal component of the neurofibrillary lesions (41). 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). 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).Tau is expressed predominantly in neurons and at lower levels in astrocytes and oligodendrocytes (143). Moreover, in some diseases, tau also forms aggregates in glial cells and these can outnumber neurons with aggregates (48). Tau contains a particularly high content of serines and threonines, many of which are phosphorylated under physiological conditions (42). 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). Phosphorylation decreases the binding of tau to microtubules. This increases the pool of soluble tau and is thought to trigger the disintegration of microtubules (43). 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).Mutations in Tau have not been found in AD. Instead, mutations have been identifie...

Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

“…This hypothesis is supported by the accumulation of phosphorylated neurofilaments in perikarya of spinal cord motor neurons in Tg30tau mice, an event known to be associated with a variety of axonal insults, including axonal transection 62,63 and several neurodegenerative diseases, 64 such as classic amyotrophic lateral sclerosis, 65 Guam amyotrophic lateral sclerosis/parkinsonismdementia complex 48 and transgenic models. 66 Axonal spheroids were numerous in Tg30tau mice and appeared even earlier than NFTs. An axonopathy with spheroids was observed in tau transgenic lines expressing wild-type tau, 9 -11,67 but in the absence of NFTs.…”

Animal models of neurodegenerative diseases

“…16,17 APP mouse models do not develop neurofibrillary tangles and exhibit little neuronal loss, although hyperphosphorylated tau can be observed in different brain regions. 18 Mice overproducing Ab do not exhibit neurofibrillary tangles as well. However, Ab pathology can activate kinases, downregulate phosphatases, and impair tau degradation, leading to tau pathology.…”

“…As mentioned before, APP transgenic mice do not develop extensive neurofibrillary tangles, and tau remains soluble. 18 Indeed soluble tau might be more important to the disease than aggregated tau.…”

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…A number of excellent reviews on the biology and pathology of Tau have appeared over the past few years (Cassimeris and Spittle 2001;Garcia and Cleveland 2001;Terwel et al 2002;Dehmelt and Halpain 2005;Andreadis 2006;Ballatore et al 2007;Gotz et al 2007Gotz et al , 2010Schneider and Mandelkow 2008;Sergeant et al 2008;Aguzzi and Rajendran 2009;Spires-Jones et al 2009;Iqbal et al 2009;Wolfe 2009;Goedert et al 2010;Morris et al 2011;Salminen et al 2011). This brief review will cover a few salient aspects, with an emphasis on Tau structure and interactions.…”