Under Heparin-Free\nConditions Unsaturated Phospholipids\nInhibit the Aggregation of 1N4R and 2N4R Tau

A progressive aggregation of Tau proteins in the brain\nis linked\nto both Alzheimer’s disease (AD) and various Tauopathies. This\npathological process can be enhanced by several substances, including\nheparin. However, very little if anything is known about molecules\nthat can inhibit the aggregation of Tau isoforms. In this study, we\nexamined the effect of phosphatidylserines (PSs) with various lengths\nand saturations of fatty acids (FAs) on the aggregation properties\nof Tau isoforms with one (1N4R) and two (2N4R) N-terminal inserts that enhance binding of Tau to\ntubulin. We found that PS with unsaturated and short-length FAs inhibited\nTau aggregation and drastically lowered the toxicity of Tau oligomers\nthat were formed in the presence of such phospholipids. Such an effect\nwas not observed for PS with fully saturated long-chain FAs. These\nresults suggest that a short-chain irreversible disbalance between\nsaturated and unsaturated lipids in the brain could be the trigger\nof Tau aggregation.