Neurofibrillary tangles and tau phosphorylation
| Autor: | Karelle Leroy, Michèle Authelet, Jean Pierre Brion, Jean-Noël Octave, Simon Lovestone, Gunter Tremp, Nicole Touchet, R Dayanandan, Laurent Pradier, Brian H. Anderton |
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| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Gene isoform
Genetically modified mouse Microtubules -- metabolism Calcium-Calmodulin-Dependent Protein Kinases -- metabolism Transgene Tau protein Alzheimer Disease -- metabolism tau Proteins Mice Transgenic macromolecular substances CHO Cells Neurofibrillary Tangles -- metabolism Transfection Biochemistry Microtubules Presenilin Amyloid beta-Protein Precursor Glycogen Synthase Kinase 3 Mice Microtubule Alzheimer Disease Cricetinae mental disorders Presenilin-1 Animals Humans Membrane Proteins -- metabolism Neurons -- metabolism Phosphorylation Neurons Calcium-Calmodulin-Dependent Protein Kinases -- genetics Neurofibrillary Tangles -- pathology Membrane Proteins -- genetics tau Proteins -- metabolism biology tau Proteins -- genetics Glycogen Synthase Kinases Membrane Proteins Neurofibrillary Tangles Sciences bio-médicales et agricoles Cell biology Tubulin Calcium-Calmodulin-Dependent Protein Kinases biology.protein Alzheimer Disease -- etiology Neurons -- pathology Amyloid beta-Protein Precursor -- metabolism |
| Zdroj: | Biochemical Society Symposia (67 Europe PubMed Central |
| Popis: | Neurofibrillary tangles (NFTs) are a characteristic neuropathological lesion of Alzheimer's disease (AD). They are composed of a highly-phosphorylated form of the microtubule-associated protein tau. We are investigating the relationship between NFTs and microtubule stability and how tau phosphorylation and function is affected in transgenic models and by co-expression with beta-amyloid precursor protein and presenilins. In most NFT-bearing neurons, we observed a strong reduction in acetylated alpha-tubulin immunoreactivity (a marker of stable microtubules) and a reduction of the in situ hybridization signal for tubulin mRNA. In transfected cells, mutated tau forms (corresponding to tau mutations identified in familial forms of frontotemporal dementias linked to chromosome 17) were less efficient in their ability to sustain microtubule growth. These observations are consistent with the hypothesis that destabilization of the microtubule network is an important mechanism of cell dysfunction in Alzheimer's disease. The glycogen synthase kinase-3 beta (GSK-3 beta) generates many phosphorylated sites on tau. We performed a neuroanatomical study of GSK-3 beta distribution showing that developmental evolution of GSK-3 beta compartmentalization in neurons paralleled that of phosphorylated tau. Studies on transfected cells and on cultured neurons showed that GSK-3 beta activity controls tau phosphorylation and tau functional interaction with microtubules. Tau phosphorylation was not affected in neurons overexpressing beta-amyloid precursor protein. Transgenic mice expressing a human tau isoform and double transgenic animals for tau and mutated presenilin 1 have been generated; a somatodendritic accumulation of phosphorylated transgenic tau proteins, as observed in the pretangle stage in AD, has been observed but NFTs were not found, suggesting that additional factors might be necessary to induce their formation. Journal Article Research Support, Non-U.S. Gov't info:eu-repo/semantics/published |
| Databáze: | OpenAIRE |
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