Memory loss and cognitive dysfunction, two hallmarks of Alzheimer’s disease, have now been linked to low levels of one particular protein, called NPTX2.
The discovery represents a stepping-stone in the mechanisms underlying this disease, which may help in the development of new therapies. The study, “NPTX2 and cognitive dysfunction in Alzheimer’s Disease,” was published in the journal eLife.
Amyloid is a protein known to accumulate in the brain of Alzheimer’s patients, forming amyloid plaques. These protein clumps are thought to underlie the mental decline associated with the disease. However, studies imaging the brain and post-mortem analyses of brain tissue show that high levels of amyloid can occur without Alzheimer’s symptoms. These results challenge the proposed direct link between amyloid deposits in the brain and dementia.
Now, Johns Hopkins Medicine researchers and colleagues have shown that when low levels of the protein NPTX2 occur in the brain at the same time as amyloid is accumulating, it causes a disruption in the connection of neurons, leading to a failure of memory.
“These findings represent something extraordinarily interesting about how cognition fails in human Alzheimer’s disease,” Paul Worley, MD, a neuroscientist at Johns Hopkins University School of Medicine and the study’s lead author, said in a press release. “The key point here is that it’s the combination of amyloid and low NPTX2 that leads to cognitive failure.”
The NPTX2 gene is activated early in neurons and is essential for strengthening circuits in the brain.
“Those connections are essential for the brain to establish synchronized groups of ‘circuits’ in response to experiences,” Worley said. “Without them, neuronal activation cannot be effectively synchronized and the brain cannot process information.”
The researchers first analyzed a library of 144 archived human brain tissue samples. They measured the levels of NPTX2 protein and observed a staggering reduction of up to 90 percent of the protein in the brain tissue from people with Alzheimer’s compared to those without the disease. Brain tissue from people who had never shown signs of Alzheimer’s but who displayed amyloid plaques showed normal levels of NPTX2. These results support a link between NPTX2 and Alzheimer’s, an association unexplored until now.
They dissected the role of NPTX2 in cognition by studying mice engineered to not produce NPTX2. The lack of this gene per se didn’t seem to affect cell function in the brain. However, this changed when researchers inserted a gene that increases amyloid generation in the animals’ brain.
In brain slices from mice with both amyloid and no NPTX2, researchers detected a disruption in the interneurons connection important for making new memories. Looking at another protein, a glutamate receptor normally expressed in interneurons and essential for interneuron function, researchers found that its expression was decreased, similar to what occurs in human Alzheimer’s brains. The phenotype causes a state of hyperexcitability in the brain.
The results suggest a synergistic (interdependent) effect between amyloid plaques and NPTX2, which may explain why people with high levels of brain amyloid do not always develop Alzheimer’s.
Researchers went on to living human subjects and analyzed NPTX2 protein in the cerebrospinal fluid (CSF) of 60 living Alzheimer’s patients and 72 people without Alzheimer’s.
The lower memory and cognition performance in Alzheimer’s patients correlated with lower levels of NPTX2 in the CSF. Overall, NPTX2 levels in the CSF of Alzheimer’s patients showed a reduction of 36 to 70 percent when compared to people without Alzheimer’s.
Moreover, NPTX2 was also correlated with the size of a brain region – the hippocampus – essential for memory formation. In the Alzheimer’s patient population, NPTX2 was a better biomarker for cognitive performance than currently used candidates, including the protein tau and another protein, known as A-beta-42, associated with Alzheimer’s.
“Perhaps the most important aspect of the discovery is that NPTX2 reduction appears to be independent of the mechanism that generates amyloid plaques,” Worley said. “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.”
“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 concluded.
Patients with relatively high NPTX2 may benefit in a particular way from drugs that disrupt amyloid. Researchers are now collaborating with companies for the development of a commercial test that measures NPTX2 levels.