Glycosaminoglicans may link tau amyloid aggregation and abnormal phosphorylation

MEDINA, LUCIANA; VERA, CECILIA; GONZÁLEZ-LIZÁRRAGA, FLORENCIA; SEQUEIRA, SABRINA

Congreso; III Latin American Federation of Biophysical Societies (LAFeBS) ? IX IberoAmerican Congress of Biophysics ? XLV Reunion Anual SAB 2016; 2016

Tau is a microtubule-associated protein that plays a crucial role in regu-lating microtubule dynamics, axonal transport and neurite outgrowth. Inphysiological conditions, these functions are regulated by site-specificphosphorylation. In pathological conditions, abnormal phosphorylationand amyloid aggregation lead to the formation of neurofibrillary tan-gles (NFT), a neuropathological hallmark in Alzheimer?s disease brain.The relationship between phosphorylation and aggregation is not wellunderstood and could be essential to understand the toxic transition ofTau.In this work we study extracellular glycosaminoglicans as the link be-tween phosphorylation and amyloid aggregation. In Alzheimer?s dis-ease, heparan sulphate (HS) accumulates at the intracellular level inneurons co-localizing with the NFT, while they persist at the neuronalcell membrane in normal brain. It is described that the presence of gly-cosaminoglycans like heparin or (HS) is needed to achieve the patho-logical phosphorylation profile. Using fluorescence, infrared and SAXSspectroscopy we analyzed tau conformational changes alone and in thepresence of these sugars in order to understand the molecular eventsleading to aggregation. The protein alone is not prompt to aggregate,remaining stable over the time. However, in the presence of heparin orHS, aggregation as monitored by ThT follows a sigmoidal kinetics. Af-ter 24 h, both oligomers and amyloid fibrils are observed by TEM. Sur-prisingly, SAXS and FTIR data showed significant difference betweenheparin and HS prefibrillar aggregates. These results strongly suggestthat glycosaminoglycans are able to induce conformational changes inTau leading to abnormal phosphorylation and generation of novel toxicoligomeric species.