EAPSI: Understanding Alzheimer's Disease through Modifying the Electrical Stability between Two Key Amino Acids of an Important Protein

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Alzheimer's disease (AD) is a progressive, neurodegenerative disease that affects 5 million elderly Americans and this number is expected to triple by 2050. AD is currently the 6th leading cause of death in the United States. Despite decades of AD research, there is no cure for this deadly disease. A significant challenge in AD research is studying the mechanism that makes an ordinary protein transform from its natural, non-toxic state to an abnormal, toxic form. Often, differences in protein structure can lead to drastically altered biological activities. Unfortunately, this rapid transition between the two distinct structural identities is not well understood. Experimental evidence suggests that there are favorable molecular interactions that stabilize the abnormal form. This award supports research that aims to study the electrical interaction between two key amino acids of an important AD protein, amyloid-beta, in order to evaluate the protein's structural stability. The research will be conducted at National Taiwan University under the mentorship of Dr. Richard Cheng, whose expertise in one of the experimental techniques will be critical to the outcome of the project.The experimental design of this basic Alzheimer's disease research integrates the specialties from both the home and host laboratories. A series of peptide structural models of amyloid-beta will be synthesized using standard solid-phase peptide synthesis followed by product purification and characterization. These synthetic peptides will incorporate fragments of amyloid-beta that are known to initiate uncontrolled aggregation which can be subsequently suppressed by a well-placed hydrogen-bond blocker. To probe the electrostatic interaction between two key amino acids (lysine and glutamic acid) of amyloid-beta, they will be systematically replaced by amino acid derivatives. The modifications should either enhance or reduce the electrostatic interaction, which can lead to structural stabilization or destabilization of these peptides, respectively. Circular dichorism spectroscopy, a specialty of Dr. Cheng, will be used to quantify the stabilizing energies. The results of this project will afford deeper insights of a key molecular interaction that can stabilize the toxic form of amyloid-beta. This information may assist other AD researchers in their own endeavors and lead to future Alzheimer's disease discoveries that will benefits society. This NSF EAPSI award supports the research of a U.S. graduate student and is funded in collaboration with the Ministry of Science and Technology of Taiwan.