Effect of trehalose on Alzheimer's Amyloid Beta (1-40) - membrane interaction

SANTOSH REDDY; ASLIN IZMITLI; CAROLINA SCHEBOR; JUAN J. DE PABLO

Salt Lake City

Congreso; AIChE ANNUAL MEETING.; 2007

As many as nine neurodegenerative disorders, including Huntington´s disease (HD), have been associated with the aggregation of proteins containing an expanded polyglutamine tract. Nuclear inclusions formed by these aggregates are found in the postmortem brains of patients suffering from these diseases. The current work aims to provide an understanding of the mechanism leading to this phenomenon, evaluate the different controlling parameters and examine possible methods to inhibit it. To this end, atomistic molecular dynamics simulations in implicit solvent are employed to determine the nucleus in polyglutamine aggregation and the ability of a single beta helical structure of polyglutamine to seed the aggregation process. The effect of cosolutes and ions on the stability of the nucleus is examined. It is found that the nucleus is significantly stabilized in the presence of Trehalose and Glucose, two disaccharides commonly used as bioprotectants. In contrast, ions like calcium and potassium destabilize the structure. The detailed mechanism of formation of a nucleus from a random coil state is unraveled with Transition Interface Sampling simulations, and the transition states involved in the formation of nucleus are identified.