Abnormal accumulation and deposition of the amyloid ss-protein (Ass), a prominent pathological feature of patients with Alzheimer's disease (AD) and related disorders, can occur from increased production but in most cases is likely due to decreased clearance mechanisms in the CNS. Clearance mechanisms involve factors that can promote Ass efflux from the CNS, enhance Ass degradation, and/or inhibit Ass assembly and deposition. Although much has been learned about specific molecules that can either influence Ass assembly and deposition or enzymes that can proteolytically degrade Ass our understanding of these processes in brain remains incomplete. Recently, we identified myelin basic protein (MBP) as a novel factor in brain that can bind Ass and potently inhibit its assembly into fibrils. Furthermore, through the course of our recent studies we made the exciting new discovery that MBP, with recently reported serine proteinase activity, can also proteolytically degrade Ass peptides. In light of these novel findings the hypothesis that forms the basis of this proposal is that MBP may contribute to the regulation of Ass levels, amyloid formation, and deposition in brain through its respective proteolytic and fibril-inhibiting activities. The broad objective of this proposal is to better understand these novel activities of MBP that involve its interaction with Ass peptides.
The specific aims of the proposal are as designed to: 1) determine the respective binding regions on MBP and Ass peptides and investigate the consequences of this interaction, 2) characterize the proteolytic activity of MBP and its degradation of Ass, and 3) determine if MBP can modulate Ass levels and amyloid deposition in cell culture models. In the present proposal we plan to implement a multi-faceted approach to investigate how MBP interacts with Ass peptides to regulate their assembly and degradation. We will utilize a combination of biochemical, molecular, ultrastructural, and cell culture approaches to understand these interactions and the consequences of them.
Aggregation and deposition of a protein fragment, known as amyloid ss-protein (Ass), in the brain is a key pathological feature of Alzheimer's disease and related disorders. Factors that regulate its degradation and aggregation play an important role in determining if Ass accumulates during disease. The purpose of this proposal is to investigate a newly identified factor known as myelin basic protein (MBP) that can promote Ass degradation and prevent its aggregation and deposition in brain. Completion of these studies will provide new insight into MBP interactions with Ass that may contribute to the regulation of Ass levels, assembly, and deposition in brain that occur in Alzheimer's disease and related disorders. This is a completely novel area of research with virtually nothing known outside of the work we have initially accomplished in our laboratory. Importantly, these newly identified activity of MBP may lead to the development of new therapeutic approaches to combat pathological= Ass accumulation and deposition that occurs in Alzheimer's disease and related amyloid depositing diseases.
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