Nonphosphorylated tau slows down Aβ(1–42) aggregation, binds to Aβ(1–42) oligomers, and reduces Aβ(1–42) toxicity

The formation of neurofibrillary tangles and amyloid plaques accompanies the progression of Alzheimer's disease. Tangles are made of fibrillar aggregates formed by the microtubule-associated protein tau, whereas plaques comprise fibrillar forms of amyloid-beta (Aβ). Both form toxic oligomers during aggregation and are thought to interact synergistically to each promote the accumulation of the other. Recent in vitro studies have suggested that the monomeric nonphosphorylated full-length tau protein hinders the aggregation of Aβ(1–40) peptide, but whether the same is true for the more aggregation-prone Aβ(1–42) was not determined. We used in vitro and in vivo techniques to explore this question. We have monitored the aggregation kinetics of Aβ(1–42) by thioflavine T fluorescence in the presence or the absence of different concentrations of nonphosphorylated tau. We observed that elongation of Aβ(1–42) fibrils was inhibited by tau in a dose-dependent manner. Interestingly, the fibrils were structurally different in the presence of tau but did not incorporate tau. Surface plasmon resonance indicated that tau monomers bound to Aβ(1–42) oligomers (but not monomers) and hindered their interaction with the anti-Aβ antibody 4G8, suggesting that tau binds to the hydrophobic central core of Aβ recognized by 4G8. Tau monomers also antagonized the toxic effects of Aβ oligomers in Caenorhabditis elegans. This suggests that nonphosphorylated tau might have a neuroprotective effect by binding Aβ(1–42) oligomers formed during the aggregation and shielding their hydrophobic patches.