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Alzheimer's may stem from defective genes

Staff Report

U.Va. Health System researchers have linked the abnormalities in the function of Alzheimer's mitochondrial genes, first described by U.Va. scientists in 1997, to one of the characteristic abnormalities found in the brains of patients with Alzheimer's disease.

Mitochondria are the batteries of the cells that provide usable energy. Their genes are small pieces of circular DNA that are passed from mother to children. Abnormalities in mitochondrial genes have been associated with rare brain diseases in children and adults.

"As a result of this study we are now much closer to understanding how Alzheimer's develops in the 90 percent of patients who have the so-called 'sporadic form' that tends to appear in those without a strong family history of the disease," said Dr. James P. Bennett Jr., a neurologist at U.Va.'s Center for the Study of Neurodegen-erative Diseases and principal investigator of the research, published in the August issue of Annals of Neurology.

Alzheimer's, which effects an estimated 3 million to 5 million Americans, is characterized by two changes that show up in the diseased brain tissue: chemical deposits, or plaques, that consist of degenerating nerve cells combined with a form of protein called beta amyloid; and malformations within nerve cells, called neurofibrillary tangles. Bennett's team linked the plaques with the mitochondrial abnormalities.

Although a pharmaceutical company recently announced it had begun testing a vaccine for Alzheimer's on human patients, Bennett said the vaccine won't prevent the process, but because it removes the plaques, it might be helpful in preventing the symptoms.

"We show that a likely source of increased secretion and deposition of beta amyloid in the brains of Alzheimer's patients derives from the defects in mitochondrial function induced by defective mitochondrial genes," said Bennett, whose 12-person research team includes professors, technicians, graduate and undergraduate students.

Bennett's colleague, Dr. W. Davis Parker Jr., advanced the theory of mitochondrial genes' role in Alzheimer's about 10 years ago and was instrumental in developing the cybrid cell model used by the U.Va. team in its current study.

Using cell systems, or cybrids, made from platelet mitochondria of five subjects with Alzheimer's and five normal control subjects, the U.Va. researchers examined amyloid metabolism and mitochondrial function.

"The mechanism of how the over-secretion of beta amyloid protein occurs can be traced back to mitochondria [with abnormal genes] that cause cell death pathways to be activated. That leads to amyloid plaque buildup inside and outside the nerve cells," Bennett said.

The cell death pathways include enzymes known as "caspaces" that, when activated, can break down many important cell proteins. The U.Va. group showed that Alzheimer's mitochondrial genes caused more caspace activation, and the caspaces in turn caused more beta amyloid proteins to be formed.

The plaques found in the brains of people with Alzheimer's appear to build up because the mitochondria become less efficient, due to the abnormal genes, as well as because of the effects of aging. This can come about because the abnormal genes also reduce the mitochondria's ability to process oxygen efficiently in the cell. The mitochondria normally change oxygen into water, but when they work less efficiently, electrons that would become part of the water molecules spin off as "oxygen-free radicals" that attack the cells.

Although the mitochondria create energy for cells by maintaining a small electrical charge -- about one-tenth as large as a standard flashlight battery -- they are also responsible for restraining proteins that can activate caspaces and other cell death pathways. Impaired by increased oxygen-free radical attacks, the Alzheimer's mitochondria start losing their charge and are more likely to allow these cell-death-initiating proteins to leak out.

The U.Va. team showed that applying drugs that absorbed the oxygen-free radicals helped Alzheimer's mitochondria restore their electrical charge, and that inhibiting caspaces blocked the excessive beta amyloid production.

"Finding out what causes Alzheimer's damage to brain cells provides possible avenues for new research," Bennett said. "The cell model could be used to develop drugs to reverse the process or to soak up the oxygen-free radicals and prevent mitochondrial damage."

 


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