Exchangeable GTP binding site of the beta-subunit of brain tubulin in Alzheimer disease.

A major cytoskeletal and molecular change of yet unknown mechanism is the accumulation of argentophilic neurofibrillary tangles in certain selected neurons of the aged human brain, especially the Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT). Increasing evidence suggests an association between neurofibrillary tangles and a defective microtubule (MT) assembly in AD/SDAT brain. Tubulin, the basic unit of MT is an alpha-beta heterodimer protein of about 55,000 molecular weight each. The beta subunit of tubulin has an exchangeable (E) binding site for guanosine triphosphate (GTP) which in the presence of microtubule-associated proteins (MAPS) promotes the MT assembly. The 8-azido GTP, a photoaffinity analog of GTP, which has been proven to mimic the natural ligand in promoting MT assembly, was used to examine the GTP binding of beta- tubulin in AD brain. Preliminary studies revealed a minimal photoinsertion into the beta-subunit of tubulin in AD/SDAT brain homogenate. Furthermore, the exchangeable GTP binding site was also unavailable in brain tubulin isolated from most of the AD/SDAT cases.