Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau

Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: Sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau

^*Departmento de Química Biológica, Facultad de Ciencias Químicas, Centro de Investigaciones en Química Biológica de Córdoba, C.C.61, 5000-Córdoba, Argentina; and ^†New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314

Abstract

The microtubule-associated protein (MAP) tau is abnormally hyperphosphorylated in Alzheimer disease and accumulates in neurons undergoing neurofibrillary degeneration. In the present study, the associations of the Alzheimer-hyperphosphorylated tau (AD P-tau) with the high molecular weight MAPs (HMW-MAPs) MAP1 and MAP2 were investigated. The AD P-tau was found to aggregate with MAP1 and MAP2 in solution. The association of AD P-tau to the MAPs resulted in inhibition of MAP-promoted microtubule assembly. However, unlike the coaggregation of AD P-tau and normal tau, the association between AD P-tau and the HMW-MAPs did not result in the formation of filaments/tangles. The affinity of the tau–AD P-tau association was higher than that of HMW-MAPs–AD P-tau because normal tau inhibited the latter binding. The association between AD P-tau and the HMW-MAPs also appeared to occur in situ because these proteins cosedimented from the Alzheimer brain extracts, and, in the sediment, the levels of the HMW-MAPs correlated with the levels of AD P-tau. These studies suggested that the abnormally phosphorylated tau can sequester both normal tau and HMW-MAPs and disassemble microtubules but, under physiological conditions, can form tangles of filaments only from tau.

Footnotes

↵ ‡ To whom reprint requests should be addressed. e-mail: kiqbal{at}admin.con2.com.
Dominick P. Purpura, Albert Einstein College of Medicine, Bronx, NY
Abbreviations: AD, Alzheimer disease; PHF, paired helical filaments; MAP, microtubule-associated protein; HMW-MAP, high molecular weight MAP; AD P-tau, AD-hyperphosphorylated tau.