Medical researchers at the University of
Virginia Health System have succeeded in directly linking the brain cell damage
and death that are hallmarks of Alzheimer's disease (AD) to abnormalities in
mitochondrial genes.
Mitochondria, which are descended from primitive bacteria, are the
"powerhouses" of our 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. This study shows that defective mitochondrial
genes may cause Alzheimer's, the most common degenerative brain disease in
adults. "For us, this is a major finding," said Dr. James P. Bennett
Jr., a neurologist at U.Va. and principal investigator of the study. "We
show that a likely source of increased secretion and deposition of beta amyloid
in the brains of AD patients derives from the defects in mitochondrial function
induced by defective AD mitochondrial genes."
Using cell systems or cybrids made from platelet mitochondria of five sporadic
AD subjects and five age-matched, neurologically normal controls, the U.Va.
researchers examined amyloid metabolism and mitochondrial function in the
disease. "Prior work on amyloid secretion centered on the rare inherited
forms that account for only about 10 percent of the cases," Bennett said.
"We built our cybrids using mitochondria from people with sporadic or
non-familial AD, which accounts for more than 90 percent of AD cases."
They found that the defective mitochondrial genes in AD cybrid cells caused
increased damage from oxygen free radicals ("oxidative stress"),
because of the inefficient processing of oxygen into water. This led to the
activation of cell death pathways, which resulted in the over secretion of beta
amyloid peptides and the forming of plaque-like areas in the cells. Blocking
the activation of cell death pathways eliminated the abnormal beta amyloid
secretion.
AD, which effects an estimated three to five million Americans, is
characterized by two changes in the brain tissue: senile or neuritic plaques,
chemical deposits consisting of degenerating nerve cells combined with a form
of protein called beta amyloid, and neurofibrillary tangles, malformations
within nerve cells. The plaques found in the brains of people with Alzheimer's
appear to be made, in part, from protein molecules -- amyloid precursor protein
or APP - that normally are essential components of the brain. Plaques are made
when an enzyme snips APP apart at specific places and then leaves the fragments
or beta amyloid in brain tissue, where they come together in abnormal deposits.
The latest findings by Bennett and his colleagues reinforce their view that
beta amyloid plaque formation is an effect, or marker, of an underlying cause.
"As a result of this study we are now much closer to understanding how AD
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,"
Bennett said. "Our findings in these AD patients firmly link together
defective mitochondrial genes and abnormal beta amyloid metabolism, which is
the biochemical hallmark of the disease. "Finding out what causes AD's
damage to brain cells provides possible avenues for new research, and hopefully
the development of drugs that will reduce the abnormal oxidative stress in the
mitochondria. If we can lessen cell death in AD brains, we should be able to
slow the progression of the debilitating symptoms of this tragic disease."