New Scholar Award in Aging
Mayo Clinic, Jacksonville
Presenilins and Gamma-Secretase Cleavage of the Amyloid Beta Protein Precursor
Dr. Golde compares Alzheimer's disease (AD) to atherosclerosis. Both are diseases associated with aging, both have strong genetic components, and both are diseases of deposition. Atherosclerosis involves deposition of cholesterol within blood vessels, which damages the cardiovascular system. Alzheimer's disease involves excessive deposition of a protein called the amyloid b
protein (Ab) in the brain. Like many who study AD, Dr. Golde believes that lowering Ab levels may delay or prevent AD akin to the way in which lowering cholesterol levels reduces the risk of developing atherosclerotic disease.
The focus of Dr. Golde's work is to find new ways to slow or prevent the deposition of the Ab . As part of this effort, Dr. Golde and colleagues are using novel genetic systems and more traditional approaches to better understand the ways in which the Ab is generated. Because Ab is initially made as a larger precursor protein, it must be "cut out" from its precursor by other proteins, generically referred to as proteases, that act as "molecular scissors". In fact, for Ab generation to take place two sequential proteolytic cleavages must occur. While the proteases responsible for the first cleavage, known as the g-secretase cleavage, have recently been cloned, the proteases responsible for the second cleavage referred to as the g-secretase cleavage remain unidentified. Significantly, other proteins called presenilins (PSs) identified by studies of genetic forms of AD, have been reported to be the elusive g-secretases. Over the past few months our laboratory has generated data that shows PSs cannot be g-secretases, but somehow regulate the g-secretase cleavage. In the future, using knowledge gained from these studies we hope to identify the protease that make the g-secretase cleavages.
Although PSs are not the g-secretase, impairing PS function can decrease Ab production. Thus, PSs, like g-secretase and the enzymes responsible for g-secretase cleavage, are therapeutic targets in AD as interfering with the function of each will decrease Ab production. However, because PSs have been shown to be important proteins that regulate many cellular functions, it is not currently known whether targeting PS will turn out to be a viable therapeutic strategy for the treatment or prevention of AD. Over the next year, using funds provided by the Ellison Medical Foundation, we will directly test whether PS are a therapeutic target by decreasing PS expression in an animal model of AD. To accomplish this we will treat the mice with peptide nucleic acids (PNA) that are designed to specifically lower PS expression. By monitoring the effects of PNA treatment on Ab production and deposition, as well as determining whether the treatment is well tolerated, we should gain significant insights into the feasibility of targeting PS for the treatment or prevention of AD. Moreover, if successful these studies will have broad reaching implications, as they would be the first demonstration that PNAs targeting a specific gene can influence the development of disease in an animal model.