Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules

Microtubule–associated protein tau becomes abnormally hyperphosphorylated in Alzheimer's disease (AD) and accumulates as tangles of paired helical 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 filaments 3.3 ± 0.7 nm in diameter. These tangles, which are not detected in identically treated normal tau or AD P–tau alone, are made up of filaments several microns in length and are labeled with tau antibodies. Dephosphorylation with alkaline phosphatase abolishes the ability of AD 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 degeneration of the affected neurons in AD.