The accumulation of abnormal tau filaments is a pathological hallmark of many neurodegenerative diseases. In 1998, genetic analyses revealed a direct linkage between structural and regulatory mutations in the tau gene and the neurodegenerative disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17). Importantly, the FTDP-17 phenotype is transmitted in a dominant rather than a recessive manner. However, the underlying molecular mechanisms causing disease remain uncertain. The most common molecular mechanism generating dominant phenotypes is the loss of function of a multimeric complex containing both mutant and wild-type subunits. Therefore, we sought to determine whether tau might normally function as a multimer. We co-incubated 35 S-radiolabeled tau and biotinylated tau with taxol stabilized microtubules, at very low molar ratios of tau to tubulin. Subsequent covalent cross-linking followed by affinity-precipitation of the biotinylated tau revealed the formation of microtubule-dependent tau oligomers. We next used atomic force microscopy to independently assess this conclusion. Our results are consistent with the hypothesis that tau forms oligomers upon binding to microtubules. In addition to providing insights into normal tau action, our findings lead us to propose that one mechanism by which mutations in tau may cause cell death is through the formation of tau complexes containing mutant tau molecules in association with wild-type tau. These wildtype-mutant tau complexes may possess altered biological and/or biophysical properties that promote onset of the FTDP-17 phenotype, including neuronal cell death by either altering normal tau-mediated regulation of microtubule-dependent cellular functions and/or promoting the formation of pathological tau aggregates.The microtubule-associated protein tau, localized predominantly in the cell bodies and axons of neuronal cells, is necessary for the establishment of neuronal cell polarity and axon outgrowth, for axonal transport, and the maintenance of axonal morphology (for example, see Refs. 1-6). Tau is also expressed in glial cells (7), although its role (8) there are less defined.Mechanistically, tau is well known to stimulate MT 1 polymerization, to stabilize MTs, and to modulate MT dynamics (9 -12). Since MT dynamics must be tightly regulated for cells to function and remain viable (e.g. see Refs. 13 and 14), it follows that tau action must also be finely regulated in cells.Alternatively, abnormal tau behavior is often associated with neurodegenerative diseases. In Alzheimer's disease, FTDP-17 and a large number of additional "tauopathies," necrotic neurons possess abnormal pathological fibers composed primarily of hyperphosphorylated and dysfunctional tau (for a recent review, see Ref. 15). Until recently, the relationship between tau and these various diseases was only correlative. However, in 1998, several groups reported a direct genetic linkage between mutations in the tau gene and FTDP-17, a group of related neurodegenerative con...