A new potential therapeutic target for Alzheimer’s disease

Like amyloid plaque, the APOE4 genetic variant has long been associated with Alzheimer’s disease, but little is known about the role the gene plays in the disease process.

Now a new study published in Natural aging not only sheds light on how the gene can trigger a cascade of pathologies that contribute to Alzheimer’s disease, but also suggests a new treatment target that could help people with the APOE4 gene in the early and late stages of the disease. Researchers at USC’s Keck School of Medicine have found that APOE4 is associated with the activation of an inflammatory protein that causes a breakdown of the blood-brain barrier that protects the brain.

This research builds on a recent USC study that found that APOE4 triggers leaks in the blood-brain barrier in humans, allowing toxic substances to pass through the body. blood circulation in the brain, damaging brain cells and disrupting cognitive functions. This process causes memory problems in patients whether or not their brains show signs of amyloid-β, the sticky plaque peptide considered a hallmark of the disease.

The latest findings also suggest a potential new treatment to slow or prevent the cognitive decline associated with Alzheimer’s disease in patients carrying the APOE4 gene, regardless of amyloid-β pathology.

“We are focusing more on therapeutic targets in blood vessels that could provide innovative treatments for people with Alzheimer’s disease, both in the early and late stages of the disease. Current findings in mouse models may be particularly promising for the treatment of advanced disease in the presence of advanced amyloid-β pathology, ”said Berislav Zlokovic, MD, Ph.D., director of the Zilkha Neurogenetic Institute from USC’s Keck School of Medicine. .

The role of APOE4, pericytes and cyclophilin A in Alzheimer’s disease

APOE4 has been shown to accelerate the breakdown of the blood-brain barrier by damaging the pericytes, a layer of cells that strengthen and protect the brain capillaries that make up the blood-brain barrier. This degradation is also associated with higher levels of cyclophilin A, a pro-inflammatory protein, in the brain vessels of patients with Alzheimer’s disease with the APOE4 gene.

In this study, USC researchers focused on cyclophilin A in mice with the APOE4 gene, which carries a high risk of Alzheimer’s disease, and mice with the APOE3 gene, which carries a medium risk of Alzheimer’s disease. Alzheimer’s disease. Cyclophilin A is found in pericytes and controls the strength of blood vessels to maintain the integrity of the blood brain barrier. In APOE4 mice, researchers found that cyclophilin A activates an enzyme that degrades blood-brain barrier blood vessels, matrix metalloproteinase 9 (MMP9). This did not happen in mice with the APOE3 gene.

The researchers then tried to treat the APOE4 mice with an inhibitor known to suppress cyclophilin A. The inhibitor not only improved the integrity of the blood-brain system. fence in APOE4 mice, but also prevented the development of further neural loss and behavioral deficits. The researchers observed that APOE4 mice treated with the inhibitor did not exhibit behavioral deficits during daily activities. This suggests that treatment targeting this pathway may also slow the progression of vascular and neurodegenerative disorders in people with Alzheimer’s disease who have the APOE4 gene.

“Until now, there was little hope for people with advanced disease, which is very hard on patients and their loved ones,” Zlokovic said. “We are delighted to further explore the potential of interventions focusing on blood brain barrier repair and strength of blood vessels, regardless of amyloid pathology, may have the effect of slowing or stopping neurodegeneration and cognitive decline in advanced Alzheimer’s disease.

The inhibitor used in this study to suppress cyclophilin A, Debio-025, was used in humans to treat hepatitis C, suggesting that it could be a potential treatment for cognitive impairment in APOE4 carriers who exhibit early or late cyclophilin A-MMP9 pathway activity disease steps.