By Morgan Nwanguma
Drug Shown to Protect the Brain’s ‘Guardian’
More than 55 million people worldwide are affected by dementia caused by Alzheimer’s disease (AD) and other neurodegenerative disorders that damage brain and nerve cells. While no effective treatment currently exists to manage or slow these conditions, researchers from Case Western Reserve University, University Hospitals, and the Louis Stokes Cleveland VA Medical Center have identified a promising new drug candidate for treating AD.
By targeting a previously unexplored mechanism in the brain, the team’s novel approach has yielded encouraging results in mouse models of Alzheimer’s. Their findings were published on May 21 in the journal Proceedings of the National Academy of Sciences (PNAS).
“Our findings suggest an effective new way to safely prevent neurodegeneration and cognitive impairment in Alzheimer’s disease by directly protecting the blood-brain barrier (BBB),” said the study’s co-lead researcher Andrew Pieper, a psychiatrist and neuroscientist at the Case Western Reserve School of Medicine and the Morley-Mather Chair of Neuropsychiatry at University Hospitals Cleveland Medical Center.
“In these mouse models treated with the drug,” he said, “the BBB remained completely undamaged. The brains didn’t undergo neurodegeneration and, most importantly, cognition and memory capacity were completely preserved.”
The collaborative study was co-led by Sanford Markowitz, the Ingalls Professor of Cancer Genetics and Distinguished University Professor at the Case Comprehensive Cancer Center, as well as the Division of Hematology-Oncology in the Department of Medicine at Case Western Reserve University and University Hospitals.
A Shift in Focus
Traditionally, neurodegenerative disease research has centered on targeting neurons. But in this groundbreaking study, researchers turned their attention to a different and often overlooked player: the blood-brain barrier (BBB). This network of specialized cells acts as the brain’s “guardian,” regulating which molecules can pass in and out of the brain while blocking harmful invaders such as bacteria and viruses.
The researchers noted that breakdown of the BBB is one of the earliest warning signs of several neurological disorders, including Alzheimer’s disease (AD) and traumatic brain injury (TBI).
Their investigation zeroed in on a specific enzyme within the immune system—15-PGDH (15-hydroxyprostaglandin dehydrogenase)—which they found to be highly concentrated in the BBB. Levels of this enzyme were even more elevated in the brains of individuals with AD, TBI, and age-related decline, suggesting that it plays a damaging role in compromising the BBB.
A Repurposed Drug Shows Promise
Focusing on 15-PGDH, the team deployed a drug known as SW033291, originally developed at Case Western Reserve School of Medicine and University Hospitals, to block the enzyme’s activity.
Interestingly, this drug wasn’t initially created for neurodegenerative diseases. Developed in the Markowitz lab with support from the Harrington Discovery Institute and the School of Medicine, SW033291 was first used to stimulate stem cell-driven tissue repair in mouse models of colitis and during bone marrow transplants.
Now, by repurposing it to protect the blood-brain barrier, researchers have opened a new and promising pathway for treating Alzheimer’s and related conditions.
“Finding together that blocking 15-PGDH also blocks brain inflammation and protects the BBB was an exciting new discovery,” Markowitz said. “Notably, SW033291 didn’t change how much amyloid — a sticky protein that accumulates in Alzheimer’s — was in the brain. This is important because the most recently approved AD drugs focus only on removing amyloid and, unfortunately, don’t work very well and have risky side effects. Inhibiting 15-PGDH thus offers a completely new approach for AD treatment.”
The researchers also discovered that blocking 15-PGDH with SW033291 protected mice from both neurodegeneration and cognitive decline following traumatic brain injury—such as a concussion—even when the drug was administered 24 hours after the injury.
Encouraged by these results, the team believes the drug holds potential not only for treating Alzheimer’s disease and brain injuries but also for a broader range of neurological disorders.
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