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.