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• W2740632497 abstract "Growing interest in the protein tau stems from its importance in neural development and cytoskeleton maintenance, as well as its key role in Alzheimer's disease (AD) and related neurodegenerative disorders. Under normal circumstances, by binding to microtubules (MT) tau regulates their stability and growing and shortening dynamics. The human protein tau is encoded by a single gene located on chromosome 17. Tau promoter activity increases significantly during neurite initiation and outgrowth. The human tau primary transcript contains 13 exons of which exons 2, 3 and 10 alternatively splice and give rise a family of six isoforms. The unique expression pattern of tau isoforms in the human central nervous system has been suggested as a possible link to the particular vulnerability of humans to neurodegenerative disorders with tauopathy, especially AD and fronto-temporal dementia (FTD). The biological activity of tau is controlled mostly by phosphorylation and, to a lesser degree, by glycosylation. In the fetal human brain, there is only one isoform referred to as fetal tau, which has three domains for binding to MT (3R). Adult tau isoforms have four MT binding domains (4R tau) and are about 40-fold more efficient at promoting MT assembly. The absence of expression of the fourth MT binding domain and high level of phosphorylation during fetal development allows for the greater cytoskeletal plasticity required for growing immature neurons. Tau phosphorylation decreases postnatally due to phosphatases activation. However, after about 35 years of age, the plasticity burden in transentorhinal and entorhinal areas, together with additional genetic dysfunction that includes both mutational (APP, PS-1 and PS-2, TAU gene) and diverse susceptibility loci (polymophisms and other genetic changes of APOE, alpha2M, alphaACT, LRP1, IL-1alpha, TNF, ACE, BACE, BCHE, CST3, MTHFR, GSKbeta and NOS3 genes, as well as in mitochondrial CO-I and CO-II genes), and environmental (e.g. head trauma) factors that interfere with synaptic plasticity (synaptic long-term potentiation, dendritic remodelling, reactive synaptogenesis), converge to a single common pathogenic pathway that causes the phosphorylation of tau to increase again. During normal aging these neurofibrillary changes remain confined mostly to neurons in layer II of the entorhinal cortex, whereas in AD, they spread into the hippocampal formation and neocortex. It has been hypothesized that the key pathogenetic event and the main mechanism that induces physical damage to axons thus compromising axoplasmic flow in AD is the fibrillogenesis of diffuse beta-amyloid deposits. Neuronal response to this kind of injury results in axonal sprouting, upregulation of tau mobilization and its excessive phosphorylation. Hyperphosphorylation promotes polymerization of tau unbound to MT and formation of straight and paired helical filaments that form neurofibrillary tangles, dystrophic neurites and neuropil threads. These pathological changes correlate with cognitive signs of dementia. Changes in tau mRNA splicing, with consequent change in protein isoform ratio (3R vs. 4R) also cause abnormal aggregation of tau. Since there is a tendency for phospho-tau proteins to 'behave' differently in the different primary dementing disorders, the phospho-tau proteins in cerebrospinal fluid (CSF) come closest to fulfilling criteria of a biological marker of AD. Stage-specific patterns of tau phosphorylation and neurofibrillary degeneration positively correlate with atrophy of hippocampal and entorhinal cortex (as revealed by MRI) and cognitive signs of dementia in AD subjects (as revealed by neuropsychological testing)." @default.
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• W2740632497 date "2007-01-01" @default.
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• W2740632497 title "Phosphorylation of tau proteins in development and Alzheimer's disease" @default.
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