Pathology of the Cleaved Tau Protein in the Context of Toxicity and the Formation of Neurofibrillary Tangles

Abstract

In Alzheimer’s disease, tau protein is abnormally processed to self-aggregate into pathologically paired helical filaments and neurofibrillary tangles. Accumulation of these structures in the somatodendritic compartment of neurons may result in pathological alterations of the cytoskeleton stability, abnormal sorting of molecules and obstruction of the intracellular transport of organelles. Initially, abnormal phosphorylation of tau was considered by many to be the major modification that alters its microtubule-binding capacity. In recent years, however, proteolytic cleavage of tau protein produced by caspases has been shown to promote the abnormal aggregation properties of tauin vitroand to produce toxic effects in cell and animal models of Alzheimer's disease. Although some of these results have been debated, truncation of tau associated with neurofibrillary tangle formation has been shown to correlate well with the clinical progression of Alzheimer’s disease. Although new alternative mechanisms of tau pathogenesis in a monomeric or oligomeric state have been proposed, the aggregated form of intact or truncated tau into insoluble polymers is still a major indicator of neuronal degeneration.