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2006 Grant - Small
Retromer-Mutant Mice as a Model of Late-Onset Alzheimer's Disease
Scott A. Small, M.D.
Columbia University Medical Center
New York, New York
2006 Investigator-Initiated Research Grant
The retromer complex is a network of proteins that transports other proteins from one part of a cell to another. Research has shown that this network may not function properly in late-onset Alzheimer's disease, the more common form of the disease that usually affects older people. During late-onset Alzheimer's, two vital components of the retromer complex, known as vacuolar protein-sorting protein 26 (VPS26) and vacuolar protein-sorting protein 35 (VPS35), may become deactivated.
In healthy cultured cells, the retromer complex transports the amyloid precursor protein (APP) from one cellular compartment called the endosome to another compartment. In studies of laboratory cells, Scott A. Small, M.D., and colleagues observed that when the retromer complex does not function properly, APP accumulates in the endosome. This lack of APP transport resulted in elevated levels of beta-amyloid, a protein fragment clipped from APP that may be a key toxic factor in Alzheimer's disease.
To explore this phenomenon in a living model, Dr. Small's team genetically engineered mice to deactivate the VPS26 and VPS35 proteins of the retromer complex. In preliminary studies, the researchers found that these mice produced high levels of beta-amyloid in their brains and experienced certain forms of memory loss. When these mice were bred with mice engineered to produce human mutated APP, the resulting offspring developed still higher levels of accumulated beta-amyloid.
Dr. Small's team will more completely study cellular properties, disease pathology and behavioral deficits in these mice in order to characterize how the dysfunction in APP transport results in increased beta-amyloid production. This work may shed new light on cellular events that contribute to late-onset Alzheimer's and suggest new therapeutic strategies for further investigation.