A team of researchers from John Hopkin’s medicine center along with other researchers across the state universities say that consequences of low levels of the protein NPTX2 in the brains of people with Alzheimer’s disease may change the pattern of neural activity in ways that lead to the learning and memory loss that are classical hallmarks of the disease by working with tissue samples obtained from brain and genetically engineered mice.
This discovery was published online in eLife, that may very soon lead to the development of new and better therapies for Alzheimer’s and other forms of cognitive decline. AD affects more than 5 million Americans currently.
Protein clumps called amyloid plaques are long seen in the brains of people with AD. These proteins are often blamed for the mental decline associated with the disease. However, autopsies and brain imaging studies reveal that people can have high levels of amyloid protein without displaying symptoms of AD, questioning the link between amyloid and dementia.
The new study:
This new study shows that when the protein NPTX2 is turned down while amyloid is accumulating in the brain, circuit adaptations that are essential for neurons to communicate are disrupted resulting in a memory failure.
The key point is that the combination of amyloid and low NPTX2 leads to cognitive failure. The gene NPTX2 is one of the immediate early genes that gets activated and makes a protein that neurons use to strengthen circuits in the brain.
Researchers studied the human brain tissue samples to measure the levels of protein encoded by the NPTX2 gene. They discovered that these protein levels were reduced as much as 90% in brain samples from people with AD compared with age-matched brain samples without AD. In contrast, people with amyloid protein who had never shown signs of Ad had normal levels of NPTX2. This was an initial suggestion of a link between NPTX2 and cognition.
Previous studies have shown NPTX 2 gene has an essential role in the development of brain wiring and for resistance to experimental epilepsy.
To study how lower than normal levels of this gene might be related to the cognitive dysfunction in AD, researchers examined mice bred without the rodent equivalent of the NPTX2 gene. Tests showed that lack of NPTX2 alone wasn’t enough to affect cell function as tested in brain samples. When researchers added to mice a gene that increases amyloid generation in their brain, it was derived that fast spiking interneurons could not control brain rhythms that are important for making new memories with both amyloid and NPTX2.
Results suggest that the increased activity seen in the brains of patients with AD is due to low NPTX2 combined with amyloid plaques with consequent disruption of interneuron function. The net effect of NPTX2 and amyloid is synergistic- one depending on the other for the effect- it would explain the cause why not all people with high levels of brain amyloid show signs of AD.
The team then examined NPTX2 protein in the CSF (cerebrospinal fluid) 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.
Also, NPTX2 corelated 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 disease 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% lower than in people with AD.
The most significant aspect of discovery is that NPTX2 reduction appears to be independent of the mechanism that generates amyloid plaques. This means that NPTX2 represents a new mechanism that is strongly founded in basic research and has not previously been studied in animal models or in the context of human disease.
NPTX2 could be applied to determine whether its measurements could be helpful in sorting patients and identifying a subset that are most responsive to emerging therapies. Drugs that disrupt amyloid may be more effective in patients with relatively high NPTX2. Researchers are providing reagents to industries to assess development of a commercial test that measures NPTX2 levels.
However, more work is needed to understand why NPTX2 levels become low in AD and how that process could be prevented or slowed down.