Tubulin Modifying Enzymes as Target for the Treatment of Alzheimer's Disease: Old Perspective With A New Angle

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Alzheimer's disease (AD) is a major cause of mental disability in the elderly, accounting for 50-60% of all dementia. While β-amyloid plaques as well as neurofibrillary tangles are neuropathological markers, inflammation plays a critical role in AD development. The aberrant detachment of microtubules (MTs) from axon MTs, cellular mislocalization, and hyperphosphorylation of tau are major factors in neurodegeneration death. Tau's ability to aggregate as well as form NFTs is assumed to be regulated by post-translational changes, which are regarded to be an essential regulatory mechanism. So far, drugs that target tau phosphorylation as well as aggregation have not shown therapeutic impact. It is now clear that tubulin PTMs cause tau dysfunction. High glutamylation and detyrosination levels in the neurons affect MT surface physicochemical characteristics. Further evidence for the relevance of such an enzymatic machinery in neurobiology comes from the recent discovery of harmful mutations in enzymes involved in surface MT modification. In this chapter, we discussed that targeting tubulin-modifying enzymes pharmacologically may be useful in treating neurodegenerative disorders.<br>