Low levels of NPTX2 protein in the brain may lead to learning and memory loss in Alzheimer's disease

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 , 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.

AD currently affects more than five million Americans.

Clumps of proteins called amyloid plaques, long seen in the brains of people with AD, are often blamed for the mental decline associated with the disease. But autopsies and brain imaging studies reveal that people can have high levels of amyloid without displaying symptoms of AD, calling into question a direct link between amyloid and dementia.

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

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 amyloid show signs of AD.

The team then examined NPTX2 protein in the cerebrospinal fluid (CSF) of 60 living AD patients and 72 people without AD. Lower scores of memory and cognition on standard AD tests, they found, were associated with lower levels of NPTX2 in the CSF. Moreover, NPTX2 correlated with measures of the size of the hippocampus, a brain region essential for memory that shrinks in AD. In this patient population, NPTX2 levels were more closely correlated with cognitive performance than current best biomarkers -- including tau, a biomarker of neurodegenerative diseases, and a biomarker known as A-beta-42, which has long been associated with AD. Overall, NPTX2 levels in the CSF of AD patients were 36 to 70 percent lower than in people without AD.

"Perhaps the most important aspect of the discovery is that NPTX2 reduction appears to be independent of the mechanism that generates amyloid plaques. This means that NPTX2 represents a new mechanism, which is strongly founded in basic science research, and that has not previously been studied in animal models or in the context of human disease. This creates many new opportunities," says Worley.

"One immediate application may be to determine whether measures of NPTX2 can be helpful as a way of sorting patients and identifying a subset that are most responsive to emerging therapies." Worley says. For instance, drugs that disrupt amyloid may be more effective in patients with relatively high NPTX2. His group is now providing reagents to companies to assess development of a commercial test that measures NPTX2 levels.

More work is needed, Worley adds, to understand why NPTX2 levels become low in AD and how that process could be prevented or slowed.



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