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Prior to the discovery of the anti-tau therapeutic antibodies resulting in several blockbuster drugs for AD, Tau was considered an unusual and poorly understood phosphoprotein that was thought to be functionally inert, based on the rather few reports that addressed tau functions. Over the past few years, there has been a rapid increase in research on tau functions. The last 2 years have also seen the explosion of interest in tau, which is now a leading candidate for drug discovery, CLINICAL PHARMACOLOGY and C>MDS. tau is known to be involved in various intracellular processes such as microtubule assembly and stabilization, axonal transport, neurogenesis and synaptic plasticity, which are all considered to play a role in both normal brain functioning, and disease pathology in tauopathies, including AD. One of the most striking observations about tau has been its selective and extended aggregation in a small set of proteins with a repeat domain, once again highlighting the paradoxical nature of tau.
When AD develops, pathological alterations are noted in the brain, such as deposition of fibrillar senile plaques (amyloid-beta), tau and neurofibrillary tangles. However, due to the complexity of the toxic cascade, and the spatial and temporal distribution of these alterations, their relationship to functional neurodegeneration is still unclear. In the past few years, a large body of evidence has shown that tauopathies may have the same pathogenesis as AD, but different clinical syndromes [38]. In addition, the accumulation of tau is described in five different neurodegenerative disorders with syndromes of motor neuron dysfunction, including the FTD, PSP, CBD and CBS. Thus, it is likely that a primary pathological process common to these disorders may be involved in the development of the respective clinical syndrome [39]. However, it is unclear whether cognitive impairment in tauopathies is due to neuronal dysfunction through the tau aggregates spread into adjacent regions, or whether the cognition impairment is independent of the tau pathology. Therefore, tauopathies are generally viewed as biomarkers rather than as curable diseases. d2c66b5586