9.Plasma Membrane-Associated PHF-Core Could be the Trigger for Tau Aggregation in Alzheimer’s Disease医学电子书.pdf

Plasma Membrane-Associated PHF-Core Could be the Trigger for Tau Aggregation in Alzheimer’s Disease Karla I. Lira-De León, Martha A. De Anda-Hernández, Victoria Campos-Peña, and Marco A. Meraz-Ríos Abstract In the present analysis, we discuss the possible role of tau in neurode- generation, 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 mem- brane anchorage signal of interferon-g receptor a -chain to the paired helical filament (PHF)-core fragment of 94 amino acids (aa) ending in glutamic 391 (IFNg R-NMF) and the second one is the PHF-core linked to the 100aa of the C-terminus of the amyloid-b protein precursor (Ab PP-C100), which contains the transmembranal domain and was named Ab -TMD-NMF. Both constructs showed thiazine red positive signal when they were cotransfected with tau441, indicating presence of b -sheet structures in cos7 cultures. In addition, when IFNg R-NMF construction was introduced in neural precursor cells primary cultures, the appearances of b -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 nuclea- tion center for PHF formation, suggesting that the abnormal localization of tau in the plasma membrane could be an early step in Alzheimer’s disease. Keywords Alzheimer’s disease , Tau, b -Sheet structures , Mislocalization , Truncation , PHFs Abbreviations AD: Alzheimer’s disease ; Ab PP : amyloid-b protein precursor; NPC: neural precursor cells ; PHFs : p