Protein CD2AP offers important clues to Alzheimer's disease

 Though Alzheimer's disease is often described as a buildup of proteins in the brain in the form of plaques and tangles, a new study by University of Calgary researchers has shown that blood vessels in the brain might hold another important clue to the disease.

The discovery, which focused on a protein called CD2AP, could dramatically change how the disease is perceived and treated, says the study's principal investigator, Dr. Minh Dang Nguyen, Ph.D., a professor in the Department of Clinical Neurosciences and a member of the Hotchkiss Brain Institute at the Cumming School of Medicine.

The research is published in the journal Neuron.

Nguyen compares the brain's vascular system to a tree. The complex branches—arteries, capillaries and veins—are critical to delivering nutrients throughout the brain. The cerebrovascular system in AD patients, he says, doesn't deliver those nutrients properly.

AD may be more related to diseases of the vascular system, such as arteriosclerosis or diabetes, than anticipated, he says.

Nguyen says the discovery reveals important factors to consider about how the brain interacts with the vascular system, and particularly, the cells that form the brain blood vessels, called brain endothelial cells. Importantly, the researchers discovered that the levels of CD2AP are reduced in brain blood vessels of patients who died with AD.

"The lower the levels, the worse their memory function was prior to death," says Nguyen. "This correlation is particularly striking in males."

The researchers dove deeper and applied what they observed in human samples to studies using mice with altered levels of CD2AP.

"We saw a lot of differences in how the vasculature was functioning related to CD2AP levels with consequences on memory function," says Dr. Milène Vandal, Ph.D., first author of the study.

In fact, says Vandal, CD2AP may be protective for females, adding to the sex-dependent result. More research into new approaches based on sex may be needed.

"If you're trying to improve the vascular system of a person to reduce their risk of AD, you might want to have different strategies for men and women, because their vascular system is just not reacting the same way," she says.

While this discovery could lead to future treatments that target CD2AP—at least in half the population—Vandal says the timeline for most new drugs is very long. Instead, the researchers say there are easier ways to reduce the risk of AD and all other vascular diseases.

"I think the immediate strategy is, really, take care of yourself and your lifestyle—anything that affects the vascular system," says Nguyen. "A good diet, exercise, less stress and better sleep—interventions that work for both sexes."

The study, led at UCalgary, involved a collaboration of researchers from Canada, the United States, Germany and Korea.

More information: Milène Vandal et al, Loss of endothelial CD2AP causes sex-dependent cerebrovascular dysfunction, Neuron (2025). DOI: 10.1016/j.neuron.2025.01.006

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