EAPSI: Understanding the Role of the Protein Cystatin C in Alzheimer's Disease

Perlenfein Tyler J, Madison WI

Investigators

Abstract

Alzheimer's disease is a neurological disorder which affects a large number of people worldwide. Though little can be done at present to treat the disease, a number of risk factors have been identified as possible drug targets. Significant evidence points to amyloid-beta, a protein fragment found in the fluid surrounding the brain, as the disease-causing agent. Abnormal behavior of this protein has been shown to result in neuron death, though the toxic pathway is poorly understood. Recently, other proteins found in the brain fluid have been shown to interact with amyloid-beta. Notably, cystatin c has been shown to bind amyloid-beta and reduce neuron death. This project will focus on understanding the manner in which cystatin c binds amyloid-beta;, which could help future researchers design more effective drugs against Alzheimer's disease. This research will be conducted in collaboration with Dr. Tamotsu Zako, a noted expert on protein interactions at Riken Research Institute in Japan. The traditional model of Alpha-beta;-related neurotoxicity follows the so-called "amyloid cascade hypothesis." In this model, low molecular weight species of alpha-beta form amyloid seeds which act as a template for rapid growth of protein filaments and fibrils. New evidence has revealed that soluble oligomeric species of alpha-beta; may be the most toxic form of this protein aggregate. Interestingly, it has been shown that cystatin c can bind and sequester alpha-beta; during the early stages of amyloid development, preventing the appearance of larger amyloid species. The mechanism of this binding is poorly understood. This project will utilize a novel dye molecule to probe for structural details of the bound protein complexes and relate that structure to possible cystatin c neuroprotective effects. This NSF EAPSI award is funded in collaboration with the Japan Society for the Promotion of Science.