Potential new treatment for Alzheimer’s disease, other neurodegenerative conditions

CLEVELAND—Worldwide, more than 55 million people suffer from dementia caused by Alzheimer’s Disease (AD) and other conditions that destroy cells in the brain and nervous system.

While there is no treatment to control or manage these neurodegenerative conditions, investigators at Case Western Reserve University, University Hospitals and the Louis Stokes Cleveland VA Medical Center have identified a new and promising drug to treat AD.

The drug—and their approach by identifying a new target in the brain—showed promising results in mouse models of AD. Their findings were reported in a study published May 21 in the scientific 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 and Division of Hematology-Oncology Department of Medicine at Case Western Reserve and University Hospitals.

New target

Historically, most research in neurodegenerative disease has focused on targeting neurons in the brain. In this study, the researchers instead identified a new target: the blood-brain barrier (BBB), a network of cells that forms a protective layer between the brain and blood.

The BBB acts as a “guardian of the brain” by allowing key molecules to enter and leave the brain, while blocking dangerous substances from the blood, including bacteria and virus. Notably, the researcher said, deterioration of the BBB is an early indicator of many forms of neurodegenerative disease, including AD and traumatic brain injury (TBI).

More specifically, the researchers targeted an enzyme in the immune system—known as 15-PGDH (15-hydroxyprostaglandin dehydrogenase)—that they discovered to be especially highly enriched in the BBB. They found that this enzyme is even further elevated in AD, traumatic brain injury and aging in both mice and humans, and that this change harms the BBB.

New drug

With 15-PGDH in the BBB as the focus, the team used a drug (SW033291) they developed at Case Western Reserve School of Medicine and University Hospitals to block the enzyme.

This enzyme-blocking drug was originally developed in the Markowitz lab with support from the Harrington Discovery Institute and the Case Western Reserve School of Medicine for an entirely different purpose. Specifically, it was first shown by Markowitz and School of Medicine Dean Stan Gerson to activate stem cells to repair tissue damage in mouse models of colitis and bone-marrow transplants.

“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 found that inhibiting 15-PGDH with SW033291 protected mice from neurodegeneration and cognitive impairment after TBI, like a concussion, even when the drug was given a full day after the injury.

Based on their results, the scientists are hopeful the drug could help treat AD, brain injuries and possibly other brain diseases.

                                                            ###

At Case Western Reserve, one of the nation's leading research universities, we're driven to seek knowledge and find solutions to some of the world's most pressing problems. Nearly 6,200 undergraduate and 6,100 graduate students from across 96 countries study in our more than 250 degree programs across arts, dental medicine, engineering, law, management, medicine, nursing, science and social work. Our location in Cleveland, Ohio—a hub of cultural, business and healthcare activity—gives students unparalleled access to engaging academic, research, clinical, entrepreneurial and volunteer opportunities and prepares them to join our network of 125,000+ alumni making an impact worldwide. Visit case.edu to learn more.

About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including five joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, Northeast Ohio Medical University, Oxford University, Taiwan National University College of Medicine and the Technion Israel Institute of Technology. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,000 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn, Facebook and Twitter. For more information, visit UHhospitals.org.

ABOUT VA NORTHEAST OHIO HEALTHCARE SYSTEM: Focusing on treating the whole Veteran through health promotion and disease prevention, VA Northeast Ohio Healthcare System provides comprehensive, seamless health care and social services for more than 141,000 Veterans across Northeast Ohio. With 17 locations of care, including 12 outpatient clinics, two community resource and referral centers, a psychosocial rehabilitation and recovery center, a chronic dialysis center, and an outpatient surgery center, VA Northeast Ohio Healthcare System’s quality services are easily accessible to Veterans in 21 counties. VA Northeast Ohio Healthcare System also contributes to the future of medicine through education, training, and research programs.

For more information about programs and services offered by VA Northeast Ohio Healthcare System, visit www.cleveland.va.gov or follow us on Facebook or Instagram @ClevelandVAMC.