Low levels of a brain protein may combine with another long-suspected culprit to trigger the learning and memory losses in Alzheimer’s disease, a study shows.
The discovery should open up important new research areas, scientists say—and may one day lead to better therapies for the disease and other forms of cognitive decline.
“The key point here is that it’s the combination of amyloid and low NPTX2 that leads to cognitive failure.”
“These findings represent something extraordinarily interesting about how cognition fails in human Alzheimer’s disease,” says Paul Worley, a neuroscientist at Johns Hopkins University School of Medicine and the senior scientist in the study.
Alzheimer’s is estimated to affect more than 5 million Americans. Clumps of proteins called amyloid plaques, long seen in the brains of Alzheimer’s patients, have often taken the blame for the mental decline associated with the disease.
But autopsies and imaging studies reveal that people can have high levels of amyloid in the brain without displaying Alzheimer’s symptoms, which calls into question a direct link between amyloid and dementia.
The new study, published in eLife, shows that when the NPTX2 gene produces less of its protein at the same time that amyloid is accumulating in the brain, circuit adaptations that are essential for neurons to work together are disrupted. That results in a failure of memory.
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“The key point here is that it’s the combination of amyloid and low NPTX2 that leads to cognitive failure,” Worley says.
Worley’s lab group studies “immediate early genes,” so called because they’re activated almost instantly in brain cells when people and other animals have an experience that results in a new memory. NPTX2 is one of these immediate early genes; it makes a protein that neurons use to strengthen “circuits” in the brain.
“Those connections are essential for the brain to establish synchronized groups of ‘circuits’ in response to experiences,” Worley says. “Without them, neuronal activation cannot be effectively synchronized and the brain cannot process information.”
Worley says he was intrigued by studies indicating altered patterns of activity in brains of people with Alzheimer’s and wondered whether altered activity was linked to changes in immediate early gene function.
To get answers, researchers first turned to archived human brain tissue samples. They discovered that NPTX2 protein levels were reduced by as much as 90 percent in brain samples from Alzheimer’s patients. Samples with amyloid plaques from people who had never shown signs of AD had normal levels of NPTX2. This was an initial suggestion of a link between NPTX2 and cognition.
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The scientists then examined mice bred without the rodent equivalent of the NPTX2 gene and discovered that a lack of NPTX2 alone wasn’t enough to affect cell function. But then they added a gene that increases amyloid generation to the mouse brains. In brain slices from mice with both amyloid and no NPTX2, fast-spiking interneurons could not control brain “rhythms” important for making new memories.
Examination of cerebrospinal fluid from 60 living Alzheimer’s patients and 72 people without the disease provided further evidence.
“Perhaps the most important aspect of the discovery is that NPTX2 reduction appears to be independent of the mechanism that generates amyloid plaques,” Worley says. “This means that NPTX2 represents a new mechanism.
One immediate application, he says, may be figuring out if NPTX2 levels can help identifying patients who can best be helped by new drugs. For instance, drugs that disrupt amyloid may be more effective in patients with relatively high NPTX2. Worley’s group is helping companies try to develop a commercial test that measures NPTX2 levels.
More work is needed, Worley adds, to understand why NPTX2 levels become low in Alzheimer’s and how to prevent or slow that process.
Others involved in the study work at Johns Hopkins; the National Institutes of Health; the University of California, San Diego; Shiley-Marcos Alzheimer’s Disease Research Center; Columbia University; the Institute for Basic Research; and the University of Exeter.
The National Institutes of Health, the Alzheimer’s Disease Discovery Foundation, and LuMind Research Down Syndrome Foundation funded the work.
Source: Johns Hopkins University
