Massachusetts Daily Collegian

The National Institutes of Health awarded a University of Massachusetts professor and two other researchers a $5 million grant to study the role of an enzyme in immune function and the pathologies of cancer, Alzheimer’s and other diseases.

Professor Barbara Osborne was awarded the grant along with Lucio Miele of Loyola University and Todd Golde — an Amherst College graduate — of the Mayo Clinic. Osborne’s lab, which will be the center of the grant, will further study the role of gamma-secretase in the immune system and the effects of inhibitors.

“We’re trying to design a therapy that’s more rational and more holistic in approach, looking at a variety of different effects that it might have on both normal and pathological situations,” said Osborne.

While examining the role of gamma-secretase in the progress of Alzheimer’s, it is easy to see it as a simple problem and according to Osborne it is common in medicine for researchers to concentrate on the impact of treatments on a disease rather than on the organism as a whole, which is part of what makes this grant fairly innovative.

“We expect that this is going to be a double-edged sword,” said Osborne. On the one hand, gamma-secretase inhibitors can arrest the progress of Alzheimer’s disease, but they can also lead to a compromise in the immune system where gamma-secretase plays an important role.

The immune system has several types of cells, including T-cells, which aid in the production of antibodies and kill other cells that have been infected by viruses and bacteria. During the course of a T-cell’s development, gamma-secretase activates the “notch” protein in nascent T-cells, which activates the protein and allows the cells to reach full maturity. Because of this role, treatments that inhibit gamma-secretase also inhibit notch, which leads to a reduced immune function.

Sometimes doctors may want to reduce the capacity of a patient’s immune system, like when they have an auto-immune disease such as lupus or rheumatoid arthritis. Osborne’s lab tested gamma-secretase inhibitors on mice with a form of multiple-sclerosis — a progressive disease where the immune system destroys the insulating sheath of neurons, making them less effective — and found that the drugs were effective in controlling the symptoms of the disease. Normally the disease manifest as paralysis in the rear appendages.

Gamma-secretase inhibitors have also been shown to slow the progress of Alzheimer’s by reducing the formation of plaques. These plaques are formed when gamma-secretase cleaves amyloid precursor protein into smaller proteins, but because Alzheimer’s is generally diagnosed after the plaques have formed, gamma-secretase inhibitor therapy cannot reverse the damage caused by the disease.

Coupled with the potential negative impact of the therapy on the immune system, this therapy looks promising for high-risk patients, those with a family history of Familial Alzheimer’s, and if more targeted delivery systems can be developed that would keep the drug from interfering with the development of the immune system.

Osborne’s work with the “notch” protein started serendipitously. A student obtained an odd result from an experiment 10 years ago where they noticed that “notch” was expressed on a white blood cell. Taking a gamble, Osborne decided to look further into the protein and its function in the immune system. While many things are still unclear about notch’s function in the development of T-cells, it is clear that this research has very profound implications.