The Effects of Osmolytes on Aβ Oligomer and Fibril Stability in Physiological Buffers

Alzheimer's disease (AD) is the most prevalent cause of dementia in the US. A pathological feature of Alzheimer's disease that is of particular interest is the deposition of the β-amyloid (Aβ) peptide. Many researchers believe that Aβ affects neurotoxicity associated with AD, and that Aβ toxicity is a strong function of peptide structure. Our goal is to develop a way to reduce the stability of the most toxic form of the Aβ peptide, the Aβ oligomer, by using a variety of small osmolytes in hopes to sway the equilibrium to form Aβ fibrils which are less toxic to cells. We will examine the stability of the oligomers and fibrils with the addition of osmolytes by measuring changes in CD absorbance. In addition, we will investigate the relative distribution of fibril, oligomer, and small soluble Aβ species before and after addition of osmolytes using a variety of biophysical methods. We believe that the results of our findings will provide strong evidence that altering the stability of Aβ would be a favorable strategy to prevent Aβ toxicity and guide the development of new therapeutics for AD.