New therapeutic target candidates for Alzheimer’s disease

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

New research published in Natural aging Not only does it reveal how this gene causes a range of conditions that contribute to Alzheimer’s disease, but it also suggests new therapeutic targets that may help people who carry the APOE4 gene in the early and late stages of the disease. Researchers at the Keck School of Medicine at USC have discovered that APOE4 is associated with the activation of inflammatory proteins that cause the destruction of the blood-brain barrier that protects the brain.

This study is based on a recent USC study that revealed that APOE4 causes leakage at the human blood-brain barrier. Blood flow It invades the brain, damages brain cells and destroys cognitive function. This process causes memory loss in the patient, whether or not the patient’s brain shows signs of amyloid-β. Amyloid β is a sticky plaque peptide that is thought to be characteristic of the disease.

The latest findings also suggest new treatments to delay or prevent Alzheimer’s disease-related cognitive decline in patients with the APOE4 gene, regardless of the pathology of amyloid-β.

“We are further focusing on therapeutic targets Blood vessels This can provide innovative treatments for people suffering from Alzheimer’s disease, both in the early and late stages of Alzheimer’s disease. Current findings in a mouse model may be particularly promising for the treatment of end-stage diseases with advanced amyloid β lesions, “said Belislav, director of the Zirka Neurogenetic Institute at the Keck School of Medicine at the USC. Zurokovich, MD, said.

Role of APOE4, pericytes, cyclophilin A in Alzheimer’s disease

APOE4 has been shown to accelerate the destruction of the blood-brain barrier by damaging the pericytes, a layer of cells that strengthen and protect the blood-brain barrier. This degradation is also associated with high levels of the pro-inflammatory protein cyclophilin A in the cerebrovascular disease of patients with Alzheimer’s disease who carry the APOE4 gene.

In this study, USC researchers focused on cyclophilin A in mice with the APOE4 gene, which is at high risk for Alzheimer’s disease, and in mice with the APOE3 gene, which is at average risk for Alzheimer’s disease. Cyclophilin A is found in pericytes and controls how strong blood vessels are to maintain the integrity of the blood-brain barrier. In APOE4 mice, we found that cyclophilin A activates matrix metalloproteinase 9 (MMP9), an enzyme that breaks down blood vessels in the blood-brain barrier. This did not occur in APOE3 gene mice.

Next, researchers attempted to treat APOE4 mice with inhibitors known to suppress cyclophilin A. Inhibitors not only improved blood-brain integrity, but also barrier APOE4 mice also prevented neuronal loss and behavioral deficits. Researchers observed that inhibitor-treated APOE4 mice showed no behavioral disorders during activities of daily living. This suggests that treatments targeting this pathway may slow the progression of vascular and neurodegenerative disease in patients with Alzheimer’s disease who carry the APOE4 gene.

“So far, there was little hope for patients in the terminal stages of illness, which is very painful for patients and their loved ones,” Zrokovich said. “I’m excited to be able to further study the potential focus of the intervention. Blood-brain barrier Regardless of the pathology of amyloid, repair and vascular strength can delay or stop the neurodegeneration and cognitive decline of advanced Alzheimer’s disease. “

The inhibitor used in this study to suppress cyclophilin A, Debio-025, has been used in humans to treat hepatitis C, which slows or early or slows cyclophilin A-MMP9 pathway activity. disease stage.