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Guanosine Triphosphate Binding to β‐Subunit of Tubulin in Alzheimer's Disease Brain: Role of Microtubule‐Associated Protein τ
Author(s) -
Khatoon Sabiha,
GrundkeIqbal Inge,
Iqbal Khalid
Publication year - 1995
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1995.64020777.x
Subject(s) - gtp' , tubulin , microtubule , alzheimer's disease , human brain , protein subunit , cytosol , biochemistry , microtubule associated protein , biology , chemistry , microbiology and biotechnology , medicine , neuroscience , disease , enzyme , gene
In Alzheimer's disease, paired helical filaments composed mainly of abnormally phosphorylated τ accumulate in certain selected neurons of the brain, and microtubules are rarely seen in the affected cells. In the present study, the binding of 32 P‐labeled 8‐azidoguanosine triphosphate ([γ‐ 32 P]8N 3 GTP), the photoaffinity analogue of GTP, to the β‐subunit of tubulin in brain homogenates was found to be markedly lower in patients with Alzheimer's disease than in aged control human cases. No significant differences were observed in the levels of the α‐ and β‐subunits of tubulin between Alzheimer's disease and control brains obtained 2–7 h postmortem. In nine of 19 Alzheimer's disease and 11 of 12 control autopsied brains (2–7 h postmortem and stored at −75°C) tubulin was isolated successfully from brain cytosol by in vitro polymerization induced with DEAE‐dextran. The GTP binding was observed in the two cycled assembled microtubule preparations from all the normal control, and in eight of nine Alzheimer's disease cases. Alzheimer's disease microtubule preparations contained varying amounts of abnormally phosphorylated τ, whereas no abnormal τ was detected in the control brain preparations. Addition of bovine τ to bovine, normal human, and Alzheimer's disease brain tubulin preparations markedly increased GTP binding to the β‐subunit. An alkaline phosphatase‐treated paired helical filament‐enriched preparation increased by approximately twofold the GTP binding to bovine brain tubulin. GTP binding to tubulin prepared by phosphocellulose chromatography of two cycled microtubules from three Alzheimer's disease and three normal control brains, revealed insignificant differences between the two groups. These findings have suggested that (1) τ protein promotes the GTP binding to the β‐subunit of tubulin, and (2) the breakdown of the microtubule system in brains of patients with Alzheimer's disease might in part be due to the abnormal phosphorylation of τ which depresses the GTP binding.