Abstract
The formation of paired helical filaments (PHF), which are composed of hyperphosphorylated Tau protein dissociating from microtubules, is one of the pathological hallmarks of Alzheimer’s disease (AD) and other tauopathies. The most important phosphatase that is capable of dephosphorylating Tau at AD specific phospho-sites is protein phosphatase 2 A (PP2A). Here we show that resveratrol, a polyphenol, significantly induces PP2A activity and reduces Tau phosphorylation at PP2A-dependent epitopes. The increase in PP2A activity is caused by decreased expression of the MID1 ubiquitin ligase that mediates ubiquitin-specific modification and degradation of the catalytic subunit of PP2A when bound to microtubules. Interestingly, we further show that MID1 expression is elevated in AD tissue. Our data suggest a key role of MID1 in the pathology of AD and related tauopathies. Together with previous studies showing that resveratrol reduces β-amyloid toxicity they also give evidence of a promising role for resveratrol in the prophylaxis and therapy of AD.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and the most prominent neurodegenerative disorder associated with aging
One of the two major pathological hallmarks of AD is the formation of paired helical filaments (PHFs), protein aggregates formed by hyperphosphorylated Tau protein that dissociates from the microtubules
Activation of phosphatase 2A (PP2A) is a promising tool in the prevention and therapy of AD and related tauopathies
Summary
Alzheimer’s disease (AD) is the most common form of dementia and the most prominent neurodegenerative disorder associated with aging. While several kinases including CDK5 and GSK3β are responsible for the phosphorylation of Tau, protein phosphatase 2A (PP2A) is the major phosphatase of Tau in the brain[3]. Reduction of both expression and activity of PP2A has been described in brains of AD patients repeatedly[4,5,6,7,8]. After complex formation MID1 mediates the ubiquitin-specific modification of PP2Ac and its degradation by the proteasome, thereby providing a highly specific microtubule-centred regulation mode for PP2A9 Substances interfering with this interaction are interesting candidates for mediating an increase in microtubule-specific PP2A activity. Resveratrol is more and more being established as a neuroprotective drug after ischemic brain injury and in neurodegenerative disorders including Parkinson’s Disease[13,14], AD15,16 and Huntington’s Disease[17,18]
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