January 6, 2004
Gene
Technique Targets Alzheimer’s Memory
Loss
CHICAGO ---
Northwestern University researchers have prevented learning and
memory deficits in a model of Alzheimer’s disease
using a gene-targeting approach to block production of beta-amyloid,
or “senile,” plaques, one of the hallmarks of the disease.
Alzheimer’s disease is a neurodegenerative condition affecting
over 15 million people worldwide that causes memory loss and, ultimately,
dementia. Some research suggests that Alzheimer’s disease
is caused by an increased amyloid burden in the brain -- the so-called
amyloid cascade hypothesis.
Results of the Northwestern study, published in the January issue
of the journal Neuron, provide compelling evidence for the therapeutic
potential of inhibiting an enzyme, beta-secretase (BACE1),
required for
the production of beta-amyloid, to treat memory impairment in
patients with Alzheimer’s disease.
The study
also presents new evidence that beta-amyloid is directly responsible
for causing the memory-robbing effects of Alzheimer’s
disease, said Masuo Ohno, research assistant professor of physiology,
Feinberg School of Medicine at Northwestern University.
Ohno’s
co-researchers on the project were John F. Disterhoft, professor
of physiology, and Robert Vassar, associate professor
of cell and molecular biology at the Feinberg School.
Ohno and colleagues
used behavioral, biochemical and electrophysiologic methods to
analyze BACE1 in mice bred to lack the enzyme but to
also overproduce amyloid precursor protein, which BACE1 “clips” into
fragments of beta-amyloid that eventually form the notorious plaques
associated with Alzheimer’s disease.
The mice were
healthy and had no serious neurological abnormalities, suggesting
that BACE1 inhibition is a rational strategy for treating
Alzheimer’s disease, Ohno said.
Importantly, the beneficial effects of BACE1 inhibition in the
mice were seen well before beta-amyloid plaques formed, indicating
that the soluble forms of the protein can disrupt learning and
memory in early stages of the disease process.
“Potential compounds that block BACE1 should be useful
in counteracting the Alzheimer’s disease process. We clearly
show for the first time that genetic reduction of brain beta-amyloid
levels prevents memory deficits and brain cell functional abnormalities
in a laboratory model of Alzheimer’s disease,” Ohno
said.
“This well-executed study in mice is another step forward
toward demonstrating the validity of anti-amyloid interventions
in Alzheimer’s disease. The next step is to see if this works
in more sophisticated models of the disease, and eventually in
humans. ” said William Thies, vice president of medical and
scientific affairs for the Alzheimer’s Association, which
funded part of the study.
The National Institutes of Health also funded the study. |