Gene targeting prevents memory loss in Alzheimer’s disease model
Northwestern University researchers have prevented learning and memory deficits in a model of Alzheimers disease using a gene-targeting approach to block production of beta-amyloid, or “senile,” plaques, one of the hallmarks of the disease.
Alzheimers disease is a neurodegenerative condition affecting over 15 million people worldwide that causes memory loss and, ultimately, dementia. Some research suggests that Alzheimers 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 Alzheimers disease.
The study also presents new evidence that beta-amyloid is directly responsible for causing the memory-robbing effects of Alzheimers disease, said Masuo Ohno, research assistant professor of physiology, Feinberg School of Medicine at Northwestern University. Ohnos 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 Alzheimers disease.
The mice were healthy and had no serious neurological abnormalities, suggesting that BACE1 inhibition is a rational strategy for treating Alzheimers 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 Alzheimers 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 Alzheimers disease,” Ohno said.
“This well-executed study in mice is another step forward toward demonstrating the validity of anti-amyloid interventions in Alzheimers 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 Alzheimers Association, which funded part of the study. The National Institutes of Health also funded the study.
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