Influence of oxidation state of lipid membranes in conformational changes of Tau and its implication in the pathogenesis of neurodegenerative diseases

SEQUEIRA, SABRINA; ÁVILA, CÉSAR LUIS; CHEHÍN, ROSANA NIEVES

Tucumán

Congreso; IIILAFeBS, IX IberoAmerican congress of Biophysics, XLV SAB Annual Meeting; 2016

Sociedad Argentina de Biofísica

Alzheimer´s disease is a progressive neurodegenerative disease that carries to a progressive lack of memory and other cognitive skills, culminating in a total and irreversible disability. Histopathologically, the Alzheimer?s disease is characterized by the presence of two distinct types of protein aggregates: extracellular amyloid deposits compound of Aβ peptide (Aβ1-42), and neurofibrillary tangles located in the intra- and extracellular spaces respectively. It is now accepted that only neurofibrillary tangles clinically correlate with the degree of dementia and are considered the most important histopathological markers in AD. These tangles are composed mainly of the protein Tau. This protein is an important component of the neuronal cytoskeleton that stabilizes microtubules, maintains the cellular shape and axonal transport. Normally Tau is phosphorylated at specific positions, but may be abnormally phosphorylated by certain kinases, losing its biological function and increasing their propensity to form amyloid aggregates. Kinases carrying out the abnormal phosphorylation would be the same kinases that produce normal phosphorylation, and the differences in the degree and type of phosphorylation would be due to conformational changes in Tau protein. The literature shows that oxidative stress is the main event during aging, and being Alzheimer closely related to aging, it was postulated that oxidative stress is the cause of neuronal death. In this work we plan to study conformational changes in Tau protein in the presence of lipid membranes submitted to peroxidation processes. For this purpose we will develop Fluorescence and Infrared Spectroscopy Assays, SAXS and Electron and Confocal Microscopy. We will also determine if the conformational changes are able to alter the protein phosphorylation profile.The results obtained will clarify basic aspects of the Alzheimer´s disease pathogenesis, constituting them as new targets for future drug development.