Cellular trafficking of pathogenic Abeta seeds in vitro and in vivo

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in aging humans, currently afflicting approximately 5 million Americans. Research recently has shown that an important feature of AD is the abnormal accumulation of specific proteins in the brain, and that the aggregation of the protein A¿ is a primary event. However, how this process of aggregation is initiated, and how the aggregates spread from one region to another, remains uncertain. The goal of our research is to understand the cellular and molecular processes that initiate the pathogenesis of AD. Our previous studies found that the deposition of A¿ can be induced, or seeded, in the brains of transgenic mouse models of AD by the infusion of dilute, A¿-rich brain extracts containing aggregated A¿. Very recently we found that A¿ aggregation can be seeded by injections of A¿-rich brain extracts into the abdominal cavity of mice. Preliminary data implicate mononuclear phagocytes (macrophages) as the vectors of the seeds, in that A¿-seed- laden macrophages enter the circulation following the intraperitoneal injection of seed. However, direct evidence for the cellular transport of the seeds into the brain is lacking. The objective of this project is to clarify the role of macrophages in disseminating the seeds for A¿ aggregation using a transgenic mouse model and in vitro models of the processing of seeds by macrophages. In the vast majority of AD cases, the factors that precipitate protein aggregation remain unknown. Understanding the cellular mechanisms underlying induced A¿ aggregation and spread could eventually point the way to new therapies for Alzheimer's disease and other debilitating brain disorders of the elderly.