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By 1999 Progress Report by the NIA/NIH • • December 13, 1999

In the past year, researchers also took several big steps toward a better understanding of the role of presenilins in AD development. Naturally occurring mutations in presenilin 1 are found in about 40 percent of people with early-onset familial Alzheimer's disease (FAD). Previous studies have suggested that these inherited gene mutations increase the total amount of beta-amyloid clipped out from the larger APP or of the longer and "stickier" form of beta-amyloid, but no one had determined how that clipping occurred, though they knew that an enzyme was involved. Researchers named this elusive enzyme gamma-secretase. Working with nerve cells grown in tissue culture, an NIA- and NINDS-supported research team at Harvard Medical School and the Brigham and Women's Hospital, Boston, gained an important insight into this process (Wolfe et al., 1999). When the investigators altered the normal sequence of presenilin amino acids (the building blocks of the presenilin protein) in two critical locations buried within the cell membrane, they found that beta-amyloid formation was reduced. This evidence strongly suggests that presenilin 1 is either gamma-secretase itself, or a unique cofactor required for gamma-secretase activity. This study is important because if its findings prove to be true, it could lead to significant advances in therapeutics research by showing investigators one exact place to intervene before plaques form.

A second, supporting study from a research team at the University of Pennsylvania, used a particular Drosophila fruit fly model to demonstrate a similar link between the presenilin protein and another protein called Notch (Ye et al., 1999). The Notch protein is a large transmembrane receptor protein involved in cell-cell interactions, especially during development. These two proteins appear to share a mechanism of regulated proteolysis (the process by which proteins are clipped to create small chains of amino acids). The researchers showed that in this fruit fly model, a proteolytic cleavage, required for Notch activity, did not occur in the absence of presenilin. Proteolysis of the human APP has similarities to Notch receptor processing and so a better understanding of presenilin function in Notch proteolysis may yield enormous dividends with respect to understanding APP processing and may lead to new insights into the development of AD.

In a collaborative study with scientists at The Johns Hopkins University and the University of Chicago, NIA intramural AD researchers also examined the effects of a deficiency of presenilin 1 on tissue culture neuronal cells isolated from genetically engineered mice (Naruse et al., 1998). They found that a lack of presenilin 1 in cortical neurons eliminated the secretion of beta-amyloid. Furthermore, this deficit in presenilin 1 caused an increase both in the accumulation of a secreted form of APP and in the buildup of certain fragments of APP within the cells. The processing of several other proteins also was affected. These results suggest that presenilin 1 plays an important role in the movement and metabolism of selected membrane and secretory proteins within cells, and this has implications for the function of presenilin 1 beyond its role in the modulation of APP processing.

NIA-supported investigators at the University of Kentucky have been exploring the role that presenilin mutations play in the death of neurons and the development of AD. In this study, the investigators used transgenic mice to demonstrate a link between a mutation in presenilin 1 and an increased susceptibility of cultured hippocampal neurons to excitotoxic injury stemming from a dose-dependent challenge with a particular kind of neurotransmitter called glutamate (Guo et al., 1999). The researchers suggest that the mechanism involved may be to increase intracellular levels of free calcium resulting in oxidative stress and the dysfunction of mitochondria. Thus, by changing the normal balance of calcium in the cells, presenilin 1 mutations may predispose neurons to multiple forms of cell death.

National Institutes of Health
National Institute on Aging

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