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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...

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Our findings suggest that topical JAK inhibitors could be developed as a potential new treatment for AA and alternative to clobetasol dipropionate 0.05% ointment.

The extent of stroke damage in patients affects the range of subsequent pathophysiological responses that influence recovery. Here we investigate the effect of lesion size on development of new blood vessels as well as inflammation and scar formation and cellular responses within the subventricular zone (SVZ) following transient focal ischemia in rats (n = 34). Endothelin-1-induced stroke resulted in neurological deficits detected between 1 and 7 days (P<0.001), but significant recovery was observed beyond this time. MCID image analysis revealed varying degrees of damage in the ipsilateral cortex and striatum with infarct volumes ranging from 0.76–77 mm3 after 14 days, where larger infarct volumes correlated with greater functional deficits up to 7 days (r = 0.53, P<0.05). Point counting of blood vessels within consistent sample regions revealed that increased vessel numbers correlated significantly with larger infarct volumes 14 days post-stroke in the core cortical infarct (r = 0.81, P<0.0001), core striatal infarct (r = 0.91, P<0.005) and surrounding border zones (r = 0.66, P<0.005; and r = 0.73, P<0.05). Cell proliferation within the SVZ also increased with infarct size (P<0.01) with a greater number of Nestin/GFAP positive cells observed extending towards the border zone in rats with larger infarcts. Lesion size correlated with both increased microglia and astrocyte activation, with severely diffuse astrocyte transition, the formation of the glial scar being more pronounced in rats with larger infarcts. Thus stroke severity affects cell proliferation within the SVZ in response to injury, which may ultimately make a further contribution to glial scar formation, an important factor to consider when developing treatment strategies that promote neurogenesis.