Researchers have discovered a likely reason why the most common form of the CD33 protein is a risk factor for Alzheimer’s disease, a finding that could open new therapeutic avenues targeting the protein, a study reports.
The protein stops brain immune cells known as microglia from wiping out beta-amyloid clumps, which are seen as a root cause of Alzheimer’s. Findings from the study, “Repression of phagocytosis by human CD33 is not conserved with mouse CD33,” could result in treatment strategies that target CD33 and shift microglia function to a protective state rather than a harmful one. The study was published in the journal Communications Biology.
This receptor has been implicated in the risk of Alzheimer’s. Prior studies have shown that a rare form of CD33 — present in fewer than 10% of the population — makes people less likely to develop Alzheimer’s disease. In contrast, the CD33 version most frequently found in people seems to have the opposite effect, contributing to Alzheimer’s susceptibility.
Increased levels of CD33 have been found in the brains of people with Alzheimer’s and correlated with disease severity and the overall load of amyloid plaques in the brain — one of the underlying causes of the disease.
A growing body of evidence suggests that CD33 controls how microglial cells — the immune cells of the brain — work, impairing their ability to clear toxic beta-amyloid protein fragments and leading to the formation of amyloid plaques.
“They can be harmful or protective,” Macauley said. “Swaying microglia from a harmful to protective state could be the key to treating the disease.”
To gather new clues about the role of CD33 in microglia, Macauley’s lab addressed the differences between mouse and human CD33 protein, since mouse models are often use to study the biological significance of genes or proteins in the context of human disease.
Previous studies have shown that human CD33 and mouse CD33 have different features; however, the functional consequences of these disparities remain poorly understood.
Using mouse and human cells grown in the lab, the team found that CD33 has species-divergent roles in regulating a key process in microglia.
Contrary to the mouse protein, the most common type of CD33 found in humans — called hCD33M — is critical to shutting down microglia’s ability to perform phagocytosis, a process by which microglia are able to engulf cells or other materials, draw them inward, and break them down.
The process is critical to keeping the brain and spinal cord healthy, because it clears dying nerve cells, microbes, and toxic products, and regulates immune responses.
Researchers saw that human CD33, contrary to the mouse protein, sends signals that block microglia from carrying out phagocytosis, preventing microglial cells from clearing out materials including beta-amyloid aggregates.
“These findings set the stage for future testing of a causal relationship between CD33 and Alzheimer’s disease, as well as testing therapeutic strategies to sway microglia from harmful to protecting against the disease — by targeting CD33,” Macauley said. “Microglia have the potential to ‘clean up’ the neurodegenerative plaques, through a process called phagocytosis — so a therapy to harness this ability to slow down or reverse Alzheimer’s disease can be envisioned.”
The study also highlights the importance of not relying on mouse CD33 for studying the receptor’s role in Alzheimer’s susceptibility in humans.
With this in mind, researchers have developed a transgenic mouse model expressing human CD33 in microglia, which “will be a valuable tool for future studies addressing the role of hCD33 [human CD33] in modulating plaque accumulation as well as pre-clinical testing of therapeutics aimed at targeting hCD33,” they said.
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