New approach to cleaning up brain waste holds promise for Alzheimer’s disease

There is growing interest in using the brain’s waste disposal system to delay or alleviate Alzheimer’s disease. Now a new technique that helps remove toxic clumps of proteins linked to Alzheimer’s disease from the brains of mice has been found to boost their performance in tests of memory and learning.

This is done by targeting a receptor called DDR2, which is more commonly researched for lung health. “If you block the DDR2 pathway, theoretically less amyloid-beta protein will be produced and at the same time it will increase the waste disposal for the protein,” he says. Jia Li at Guangzhou Medical University in China. “So we’re hoping that it can finally reverse Alzheimer’s disease.”

The accumulation of misfolded proteins known as amyloid plaques and tau tangles in the brain is thought to trigger Alzheimer’s disease. Drugs can remove amyloid clumps, but this hasn’t translated into much improvement in Alzheimer’s symptoms. Efforts are now increasingly turning to other approaches, such as boosting the glymphatic system, which removes waste from our brain.

Li and his colleagues build on this by targeting a receptor embedded in the cell membrane that enhances glymphatic action as one of its many functions. DDR2 (discoidin domain receptor 2) is being investigated Jin Su – a member of Li’s team who is also at Guangzhou Medical University – for pulmonary fibrosis. This lung condition occurs when the network of proteins surrounding cells—known as the extracellular matrix—becomes dysfunctional, resulting in the deposition of too much of the structural protein collagen, which limits the cells’ oxygen supply.

There were signs of dysfunction the extracellular matrix is ​​associated with amyloid and tau proteins that are deposited in Alzheimer’s diseasewith similar effects. “This blocking of oxygen could cause problems with thinking or remembering,” says Li.

To investigate the involvement of DDR2, the researchers began searching for it in human tissue databases and found that it was hardly ever seen. But when they looked at brain samples from people with Alzheimer’s disease, they found plenty. “We are the first to confirm that DDR2 is found in large amounts in Alzheimer’s brain tissue,” says Su.

Through a series of experiments in human and primate cells and mouse models of Alzheimer’s disease, the researchers believe that DDR2 regulates the cellular dysfunction that causes the symptoms of the disease.

This is based on the fact that three types of cells appear to increase the amount of DDR2 in their membranes during Alzheimer’s disease. The first are reactive astrocytes, which surround amyloid-beta clusters; the other is perivascular fibroblasts which change your activity before the onset of Alzheimer’s disease; and the third is the epithelial cells of the choroid plexus, which are important for the formation of cerebrospinal fluid – crucial for the glymphatic system.

These results suggest that targeting DDR2 could affect multiple aspects of Alzheimer’s disease at once, he says Shiju Gu at Harvard University. But given how complex the condition is, “I’m going to put a big question mark here when it comes to reversing Alzheimer’s,” he says.

Next, the researchers developed a monoclonal antibody to target and eliminate DDR2 receptors. In a mouse model of Alzheimer’s disease, it improved both spatial learning and memory, with brain scans showing reduced DDR2, fewer amyloid plaques and a stronger glymphatic system.

“Overall, the mouse results are encouraging and quite impressive within the capabilities of the mouse model,” says Gu. “It reiterates the importance of glymphatic function and cerebrospinal fluid dynamics to brain health. This suggests that DDR2 is a legitimate target for potential treatment of Alzheimer’s disease.”

César Cunha at the Novo Nordisk Foundation Center for Basic Metabolic Research in Denmark likes that researchers are going beyond just targeting amyloid plaques, but says the mice modeled a relatively rare type of Alzheimer’s disease that is inherited and appears earlier than usual. It’s unclear whether the antibody would work as well in the more common late-onset Alzheimer’s disease, he says.

Still, Su says DDR2 upregulation is seen in people with both familial and late-onset Alzheimer’s disease, suggesting the treatment would have broad efficacy. DDR2 expression also appears to increase with aging and hypoxiahe says, both of which are risk factors for late-onset Alzheimer’s disease.

Scientists are now conducting a clinical trial that uses the tracer to monitor DDR2 levels in the brains of people with Alzheimer’s disease to determine where to direct the antibody, Li says. They also develop a smaller antibody to cross the blood-brain barrier more effectively.

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