Effective Reduction of Tau Amyloid Aggregates in the Presence of Cyclophilin from Platanus orientalis Pollens; An Alternative Mechanism of Action of the Allergen

Abstract

A hallmark pathology of Alzheimer's disease (AD) is the construction of neurofibrillary tangles, which are made of hyperphosphorylated Tau. The cis-proline isomer of the pThr/Ser-Pro sequence has been suggested to act as an aggregation precursor according to the ‘Cistauosis’ hypothesis; however, this aggregation scheme is not yet completely approved. Various peptidyl-prolyl isomerases (PPIases) may specifically isomerize cis/trans-proline bonds and restitute Tau's ability to attach microtubules and may control Tau amyloid aggregation in AD. In this study, we provided experimental evidence for indicating the effects of the plant Cyclophilin (P-Cyp) from Platanus orientalis pollens on the Tau aggregation by various spectroscopic techniques. Our findings disclosed that the rate/extent of amyloid formation in the Tau sample which is incubated with P-Cyp decreased and these observations do not seem to be due to the macromolecular crowding effect. Also, as proven that 80% of the prolines in the unfolded protein are in the trans conformation, urea-induced unfolding analyses confirmed this conclusion and showed that the aggregation rate/extent of urea-treated Tau samples decreased compared with those of the native protein. Also, XRD analysis indicated the reduction of scattering intensities and beta structures of amyloid fibrils in the presence of P-Cyp. Therefore, the ability of P-Cyp to suppress Tau aggregation probably depends on cis to trans isomerization of proline peptide bonds (X-Pro) and decreasing cis isomers in vitro. The findings of the current study may inspire possible protective/detrimental effects of various types of cyclophilins on AD onset/progression through direct regulation of intracellular Tau molecules and provide evidence that a protein from a plant source is able to enter the cell cytoplasm and may affect the behavior of cytoplasmic proteins.