Edited by Haruki Nakamura

The Alzheimer’s disease-related protein, tau, aggregates into neurofibrillary tangles when it is hyperphosphorylated. The amino acid sequence included in the third repeat (R3) of the microtubule-binding region is suspected to be the main factor for tau aggregation. Here, we synthesized a 31-residue oligopeptide, corresponding to the R3 region, and characterized its aggregation propensity under various con-ditions. This peptide aggregated even in the absence of an aggregation-inducing molecule at a low salt concentration, while it did not form any aggregates at a high salt concen-tration. This suggests that hydrophilic interactions are the main cause of aggregation. We then investigated the func-tion of FK506-binding protein (FKBP) 12, which is known to accumulate in neurofibrillary tangles in vivo, on aggrega-tion of the R3 peptide and found that FKBP12 completely prevented the peptide from aggregating at a concentration ratio of 1: 4 (peptide:FKBP12). FKBP12 also restored the oligomer of the peptide to its monomeric status. Mutational studies on the catalytic center of FKBP12 indicated that peptidyl-prolyl isomerase activity of FKBP12 was essential for prevention of aggregation. Assuming that the propensity of aggregation of the peptide is different in each cis-/trans-isomer, we propose that the aggregation behavior of the R3 peptide can be theoretically described with a simple kinetic scheme, in which only the cis-isomer can aggregate and FKBP12 catalyzes isomerization of the peptide in both the monomeric and aggregative states