Working with human brain tissue samples and genetically engineered mice, Johns Hopkins Medicine researchers together with colleagues at the National Institutes of Health, the University of California San Diego Shiley–Marcos Alzheimer's Disease Research Center, Columbia University, and the Institute for Basic Research in Staten Island say that consequences of low levels of the protein NPTX2 in the brains of people with Alzheimer’s disease (AD) may change the pattern of neural activity in ways that lead to the learning and memory loss that are hallmarks of the disease.

This discovery, described online in the April 25 edition of the journal eLife, will lead to important research and may one day help experts develop new and better therapies for Alzheimer’s and other forms of cognitive decline.

This new study shows that when the protein NPTX2 is “turned down” at the same time that amyloid is accumulating in the brain, circuit adaptations that are essential for neurons to “speak in unison” are disrupted, resulting in a failure of memory.

“These findings represent something extraordinarily interesting about how cognition fails in human Alzheimer’s disease,” says Paul Worley, MD, a neuroscientist at the Johns Hopkins University School of Medicine and the paper’s senior author. “The key point here is that it’s the combination of amyloid and low NPTX2 that leads to cognitive failure.”

The gene NPTX2 is one of these immediate early genes that gets activated and 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,” says Worley, who is also a member of the Institute for Basic Biomedical Sciences. “Without them, neuronal activation cannot be effectively synchronized and the brain cannot process information.”

Worley says he was intrigued by previous studies indicating altered patterns of activity in brains of individuals with Alzheimer’s. Worley’s group wondered whether altered activity was linked to changes in immediate early gene function.

To get answers, the researchers first turned to a library of 144 archived human brain tissue samples to measure levels of the protein encoded by the NPTX2 gene. NPTX2 protein levels, they discovered, were reduced by as much as 90 percent in brain samples from people with AD compared with age–matched brain samples without AD. By contrast, people with amyloid plaques who had never shown signs of AD had normal levels of NPTX2. This was an initial suggestion of a link between NPTX2 and cognition.

Prior studies had shown NPTX2 to play an essential role for developmental brain wiring and for resistance to experimental epilepsy. To study how lower–than–normal levels of NPTX2 might be related to the cognitive dysfunction of AD, Worley and his collaborators examined mice bred without the rodent equivalent of the NPTX2 gene.

Tests showed that a lack of NPTX2 alone wasn’t enough to affect cell function as tested in brain slices. But then the researchers added to mice a gene that increases amyloid generation in their brain. In brain slices from mice with both amyloid and no NPTX2, fast–spiking interneurons could not control brain “rhythms” important for making new memories. Moreover, a glutamate receptor that is normally expressed in interneurons and essential for interneuron function was down–regulated as a consequence of amyloid and NPTX2 deletion in mouse and similarly reduced in human AD brain.

Worley says that results suggest that the increased activity seen in the brains of AD patients is due to low NPTX2, combined with amyloid plaques, with consequent disruption of interneuron function. And if the effect of NPTX2 and amyloid is synergistic — one depending on the other for the effect — it would explain why not all people with high levels of brain a