- Accumulation of amyloid plaques is thought to be responsible for dementia associated with Alzheimer's disease, but autopsies and brain images have revealed that there can be high levels of amyloid without displaying symptoms of AD.
- Low levels of a protein NPTX2 disrupts the memory-related neural circuits in the brain thus resulting in memory-failure or dementia, according to new findings.
- This protein is essential for the neurons to strengthen circuits in the brain, without which the brain cannot process information.
Low levels of the protein NPTX2 in the brains of people with Alzheimer's disease (AD) may be responsible for the change in pattern of neural activity. This may be the reason for learning and memory loss that are hallmarks of the disease.
A research team, from Johns Hopkins Medicine along with colleagues from 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, worked on human brain samples and genetically engineered mice, with a view to proving the role of NPTX2.
The findings could help scientists develop new and better therapies for Alzheimer's and other forms of cognitive decline.
Accumulation of clumps of proteins called amyloid plaques are often seen in the brains of people with AD and they are mostly considered responsible for the mental decline or dementia associated with the disease.
But autopsies and brain imaging studies have revealed that people can have high levels of amyloid without displaying symptoms of AD. This has questioned the direct link between amyloid and dementia.
Low Levels of Protein
When the level of protein NPTX2 reduces, simultaneously with the accumulation of amyloid plaques in the brain, there is a disruption of memory-related neuronal circuits. This in turn causes failure in memory, according to the new findings.
"These findings represent something extraordinarily interesting about how cognition fails in human Alzheimer's disease," says Paul Worley, M.D., 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."
There are a set of genes known as "immediate early genes," because they are activated almost instantly in brain cells when people have an experience which results in a new memory.
The gene NPTX2, is one such immediate early gene, 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. "Without them, neuronal activation cannot be effectively synchronized and the brain cannot process information."
Link Between NPTX2 and Cognition
Previous studies have shown that NPTX2 plays an essential role in brain wiring and for resistance to experimental epilepsy.
The team of researchers examined 144 archived human brain tissue samples. They measured the levels of the protein encoded by the NPTX2 gene.
They found that in the brain samples of patients with AD, the NPTX2 protein levels, were reduced by 90%, in comparison with age-matched brain samples without AD. But there were normal levels of NPTX2 in the brain samples of people who had amyloid plaque but never showed any sign of AD.
This suggested a link between NPTX2 and cognition.
Study in Mice
For he study, researchers mice bred without the rodent equivalent of the NPTX2 gene.
The results showed that low levels of the protein were not the only reason to affect cell function. On adding a gene that increases accumulation of amyloid plaques in the mice, sections of brain revealed that fast-spiking interneurons could not control brain "rhythms" important for making new memories.
The amyloid plaque in tandem with lower levels of the protein also down-regulated a glutamate receptor, that is normally expressed in interneurons and essential for interneuron function. It also leads to disruption of interneuron function causing increased activity in the brains of AD patients
These results explain why not all people with high levels of brain amyloid show signs of AD.
The levels of NPTX2 protein were then examined in the cerebrospinal fluid (CSF) of 60 living AD patients and 72 people without AD.
Lower levels of the protein in CSF resulted in lower scores of memory and cognition on standard AD tests.
They found that NPTX2 levels in the CSF of patients with AD were 36%-70% 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.
Further study is needed to understand the mechanism of NPTX2, why its levels become low in AD and how that process could be prevented or slowed.
The findings are published in eLife.
- About Alzheimer's Disease - (https://www.alzfdn.org/AboutAlzheimers/statistics.html)
- Paul Worley et al. NPTX2 and cognitive dysfunction in Alzheimer's Disease. eLife; (2017) doi.org/10.7554/eLife.23798