may stem from defective genes
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.
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.
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.
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.
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
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.
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
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
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.
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.
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.
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
"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