Tau phosphorylation: the therapeutic challenge for neurodegenerative disease

The microtubule-associated protein tau is integral to the pathogenesis of Alzheimer's disease (AD), as well as several related disorders, termed tauopathies, in which tau is deposited in affected brain regions. In the tauopathies, pathological tau is in an elevated state of phosphorylation and is aberrantly cleaved. It also exhibits abnormal conformations and becomes aggregated, resulting in neurofibrillary tau pathology. Recent evidence suggests that relatively early disease-associated changes in soluble tau proteins, including phosphorylation, are involved in the induction of neuronal death. Here, we summarize recent developments that suggest new therapeutic strategies to prevent or reduce the progression of pathology in the tauopathies. A list of tau phosphorylation sites identified in the tauopathies and in controls accompanies this review. The microtubule-associated protein tau is integral to the pathogenesis of Alzheimer's disease (AD), as well as several related disorders, termed tauopathies, in which tau is deposited in affected brain regions. In the tauopathies, pathological tau is in an elevated state of phosphorylation and is aberrantly cleaved. It also exhibits abnormal conformations and becomes aggregated, resulting in neurofibrillary tau pathology. Recent evidence suggests that relatively early disease-associated changes in soluble tau proteins, including phosphorylation, are involved in the induction of neuronal death. Here, we summarize recent developments that suggest new therapeutic strategies to prevent or reduce the progression of pathology in the tauopathies. A list of tau phosphorylation sites identified in the tauopathies and in controls accompanies this review. a process by which different forms of mRNA are produced from a single gene. In the case of tau, exons 2, 3 and 10 are variably included in the mature transcript for the translation of six CNS isoforms. in the context of neurodegenerative disease, amyloid is mis-folded protein that forms an extracellular aggregate with β-pleated sheet structure. In AD, extracellular deposits of Aβ are formed from amyloid precursor protein. the process of progressive loss of neurons in diseased brain. filaments of proteins deposited within neurons; a characteristic pathological feature of AD brain. enzymes that catalyse the transfer of a phosphate group from a donor, such as ATP, to a protein substrate (e.g. tau). enzymes that catalyse the hydrolysis of esters of phosphoric acid, resulting in removal of phosphate groups from proteins. neurodegenerative disease in which intracellular pathological aggregates of tau protein are present in brain. a mouse that has been genetically engineered to express a particular gene of interest.