Plasma Membrane-Associated PHF-Core Could be the Trigger for Tau Aggregation in Alzheimer’s Disease

Abstract

In the present analysis, we discuss the possible role of tau in neurodegeneration, when its intracellular normal location is altered. In order to validate our hypothesis, we used two chimeric constructs: the first one is the fusion of the membrane anchorage signal of interferon-γ receptor α-chain to the paired helical filament (PHF)-core fragment of 94 amino acids (aa) ending in glutamic 391 (IFNγR-NMF) and the second one is the PHF-core linked to the 100aa of the C-terminus of the amyloid-β protein precursor (AβPP-C100), which contains the transmembranal domain and was named Aβ-TMD-NMF. Both constructs showed thiazine red positive signal when they were cotransfected with tau441, indicating presence of β-sheet structures in cos7 cultures. In addition, when IFNγR-NMF construction was introduced in neural precursor cells primary cultures, the appearances of β-sheet structures by thiazine red signal were observed. These observations indicate that when the chimeric construct interacts either with endogenous or exogenous tau, it is capable of inducing the formation of abnormal polymerized tau. These data support the phenomena observed by Wischick et al. in vitro, and corroborate the idea of the importance of tau interacting with the membrane and the possible role as a nucleation center for PHF formation, suggesting that the abnormal localization of tau in the plasma membrane could be an early step in Alzheimer’s disease.