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.

Public Health Relevance

This application is the first attempt to investigate the role of macrophages in the processing and trafficking of pathogenic A? seeds. The key question that we will address is whether macrophages act as vectors for the spread of A?-amyloidosis by phagocytosing, translocating and releasing corruptive protein aggregates. We will approach this question by investigating the functional and pathologic consequences of the phagocytic ingestion of A? in cell culture and transgenic mouse models. The impact of these studies is that they will yield novel insights into the origins of protein aggregation in idiopathic AD and cerebral ?-amyloid angiopathy, and thus will help to illuminate the fundamental mechanisms by which neurodegenerative proteopathies are initiated and propagated in the brain. A fuller understanding of templated protein corruption in living systems could open new pathways to the treatment some of the most devastating degenerative disorders of old age.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Refolo, Lorenzo
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Emory University
Schools of Medicine
United States
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Ye, Lan; Hamaguchi, Tsuyoshi; Fritschi, Sarah K et al. (2015) Progression of Seed-Induced A? Deposition within the Limbic Connectome. Brain Pathol 25:743-52
Cintron, Amarallys F; Dalal, Nirjari V; Dooyema, Jeromy et al. (2015) Transport of cargo from periphery to brain by circulating monocytes. Brain Res 1622:328-38
Walker, Lary C; Jucker, Mathias (2015) Neurodegenerative diseases: expanding the prion concept. Annu Rev Neurosci 38:87-103
Fritschi, Sarah K; Cintron, Amarallys; Ye, Lan et al. (2014) A? seeds resist inactivation by formaldehyde. Acta Neuropathol 128:477-84
Matveev, Sergey V; Spielmann, Hans Peter; Metts, Brittney M et al. (2014) A distinct subfraction of A? is responsible for the high-affinity Pittsburgh compound B-binding site in Alzheimer's disease brain. J Neurochem 131:356-68
Jucker, Mathias; Walker, Lary C (2013) Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501:45-51
Mehta, Anil K; Rosen, Rebecca F; Childers, W Seth et al. (2013) Context dependence of protein misfolding and structural strains in neurodegenerative diseases. Biopolymers 100:722-30
Walker, Lary C; LeVine 3rd, Harry (2012) Corruption and spread of pathogenic proteins in neurodegenerative diseases. J Biol Chem 287:33109-15