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Analysis of microtubule-associated protein tau glycation in paired helical filaments
M D Ledesma1, P Bonay, C Colaço
1Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Spain.
Abstract:
Alzheimer's disease is typified by the characteristic histopathological lesions of neurofibrillar plaques and tangles. The latter are composed of paired helical filaments (PHFs), the major components of which are modified forms of the microtubule-associated protein tau. The exact nature of these modifications remains unknown, although the presence of hyperphosphorylated tau in PHFs argues strongly that phosphorylation is one of the modifications that result in the polymerization of tau into PHFs. However, hyperphosphorylation alone is insufficient to explain the formation of PHFs. In an attempt to characterize other post-translational modifications of PHF-tau, we have analyzed its glycation. A fraction of PHF-tau seems to be glycated in vivo, whereas soluble tau from either Alzheimer's disease or non-demented human brain is not glycated at all. Purified tau from bovine brain can be efficiently glycated in vitro. Tau glycation is accompanied by a decrease in the tau binding to tubulin. These results support the view that glycation may be one of the modifications hampering the binding of tau to tubulin in Alzheimer's disease, thus facilitating tau aggregation into PHFs.
Insights
Glycation, a modification of tau protein, is found in Alzheimer's disease neurofibrillary tangles. This glycation impairs tau's ability to bind to tubulin, potentially driving PHF formation.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Alzheimer's disease is characterized by neurofibrillary tangles composed of modified tau protein.
- Paired helical filaments (PHFs) are the primary component of tangles, with hyperphosphorylated tau implicated.
- Hyperphosphorylation alone does not fully explain PHF formation, suggesting other tau modifications.
Purpose of the Study:
- To investigate other post-translational modifications of PHF-tau, specifically glycation.
- To determine if tau glycation occurs in vivo in Alzheimer's disease brains.
- To assess the functional consequences of tau glycation on tubulin binding.
Main Methods:
- Analysis of PHF-tau for glycation.
- Comparison of tau glycation in Alzheimer's disease brains versus non-demented brains.
- In vitro glycation of purified bovine tau.
- Assessment of tau's binding affinity to tubulin following glycation.
Main Results:
- A portion of PHF-tau from Alzheimer's disease brains shows evidence of in vivo glycation.
- Soluble tau from both Alzheimer's and non-demented brains is not glycated.
- In vitro glycation of tau reduces its binding capacity to tubulin.
Conclusions:
- Glycation is a significant post-translational modification of tau found in Alzheimer's disease.
- Tau glycation may hinder tau-tubulin binding, contributing to tau aggregation into PHFs.
- Glycation represents a potential therapeutic target for Alzheimer's disease.