Robert Burgess, Ph.D.
Jackson Laboratory
Bar Harbor, Maine

2003 New Investigator Research Grant

Beta-amyloid protein fragments, the prime suspect in Alzheimer’s disease, aggregate by stages into amyloid plaques. Although plaques have been recognized as a pathological hallmark of the disease since German neuropsychiatrist Alois Alzheimer first described them in 1906, the molecular mechanisms underlying their formation remain poorly understood. Emerging laboratory and autopsy evidence suggests that a class of proteins with chemical characteristics called heparansulfate proteoglycans modifications (HSPGs) may bind beta-amyloid, facilitate an intermediate stage of its aggregation, and slow its breakdown and clearance from the brain. If further work bolsters evidence of these effects, HSPGs in general and one specific HSPG called agrin that looks especially promising, may offer a new pharmaceutical target.

These researchers aim to explore agrin’s behavior in a living system by genetically engineering mice that lack agrin as well as mice that produce excess agrin. Both types of mice will also produce human beta-amyloid. The hypothesis is that agrin producers will develop greater levels of plaques than those lacking agrin. If confirmed, this theory may provide evidence that HSPGs are a pharmaceutical target deserving further study.