Neurofibrillary tangles associated with Alzheimer's disease are composed ma
inly of paired helical filaments that are formed by the aggregation of abno
rmally phosphorylated microtubule-associated protein tau. 14-3-3, a highly
conserved protein family that exists as seven isoforms and regulates divers
e cellular processes is present in neurofibrillary tangles (Layfield, R., F
ergusson, J., Aitken, k, Lowe, J., Landon, NI., Mayer, R. J. (1996) Neurosc
i. Lett. 209, 57-60). The role of 14-3-3 in Alzheimer's disease pathogenesi
s is not known. In this study, we found that the 14-3-3 zeta isoform is ass
ociated with tau in brain extract and profoundly stimulates cAMP-dependent
protein kinase catalyzed in vitro phosphorylation on Ser(262)/Ser(356) loca
ted within the microtubule-binding region of tan. 14-3-3 zeta binds to both
phosphorylated and nonphosphorylated tau, and the binding site is located
within the microtubule-binding region of tan. From brain extract, 14-3-3 ze
ta co-purifies with microtubules, and tubulin blocks 14-3-3 zeta-tau bindin
g. Among four 14-3-3 isoforms tested, beta and zeta but not gamma and epsil
on associate with tau. Our data suggest that 14-3-3(zeta) is a tau protein
effector and may be involved in the abnormal tau phosphorylation occurring
during Alzheimer's disease ontogeny.