ALZHEIMERS-DISEASE HYPERPHOSPHORYLATED TAU SEQUESTERS NORMAL TAU INTOTANGLES OF FILAMENTS AND DISASSEMBLES MICROTUBULES

Microtubule-associated protein tau becomes abnormally hyperphosphoryla ted in Alzheimer's disease (AD) and accumulates as tangles of paired h elical filaments in neurons undergoing degeneration. We now show that in solution normal tau associates with the AD hyperphosphorylated tau (AD P-tau) in a nonsaturable fashion, forming large tangles of filamen ts 3.3 +/- 0.7 nm in diameter. These tangles, which are not detected i n identically treated normal tau or AD P-tau alone, are made up of fil aments several microns in length and are labeled with tau antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of A D P-tau to aggregate with normal tau and prevents tangle formation. AD P-tau disassembles microtubules assembled from normal tau and tubulin . These data provide insight into how the hyperphosphorylation of tau might lead to the formation of the neurofibrillary tangles and the deg eneration of the affected neurons in AD.