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2006 Grant - Yan
Reticulon Proteins in the Formation of Neuritic Plaques
Riqiang Yan, Ph.D.
Cleveland Clinic Foundation
2006 Investigator-Initiated Research Grant
One of the hallmarks of Alzheimer's disease is the formation of amyloid plaques in the brain. These are dense deposits of a small protein fragment called beta-amyloid, which are surrounded by damaged neurons. One of the characteristics of these neurons is small protrusions or swellings called dystrophic neurites. While neurites are normally associated with growth of neurons, these damaged neurites reflect the underlying pathology of Alzheimer's disease.
Figuring out why these dystrophic neurites form could help scientists unravel some of the mysteries of Alzheimer's disease. Riqiang Yan, Ph.D., and colleagues recently discovered that dystrophic neurites contain large amounts of reticulons, members of a poorly characterized family of proteins. Now, Yan and colleagues propose to study the links between reticulons, amyloid plaques and Alzheimer's disease.
The investigators will study which types of reticulons are associated with plaques and try to determine if the reticulons play a role in the formation of dystrophic neurites. Reticulon 3 (RTN3) is of particular interest because this protein has been shown to inhibit the process that leads to accumulation of beta-amyloid. RTN3 inhibits an enzyme called beta-secretase, which is essential for beta-amyloid production, but Dr. Yan and colleagues have also found that RTN3 proteins assemble themselves into larger structures, or polymers, that may not be capable of quelling beta-secretase.
The researchers will study the mechanisms that lead to the formation of RTN3 polymers. This may lead to therapeutics that prevent polymerization of RTN3, freeing up the protein to block beta-secretase and hence reduce the amount of beta-amyloid in the brain.