Promising New Drug Protects the Blood-Brain Barrier, Offering a Novel Approach to Alzheimer’s and Traumatic Brain Injury
Cleveland, OH – May 23, 2024 – Globally, over 55 million people live with dementia, a devastating condition often caused by Alzheimer’s Disease (AD) and other neurodegenerative illnesses. Despite decades of research, effective treatments remain elusive. Though, a groundbreaking study from Case Western Reserve University, University Hospitals, and the Louis Stokes Cleveland VA Medical Center offers a beacon of hope, identifying a novel drug and therapeutic target that demonstrably protects the brain from damage in preclinical models of Alzheimer’s and traumatic brain injury (TBI). The research, published May 21st in the prestigious Proceedings of the National Academy of Sciences (PNAS), shifts the focus from conventional neuron-centric approaches to safeguarding the critical blood-brain barrier (BBB).
The Blood-Brain Barrier: A Newly Recognized Key to Brain Health
For years, Alzheimer’s research has largely concentrated on addressing the buildup of amyloid plaques and tau tangles within the brain. While these hallmarks are undeniably present in AD, this new research suggests a critical upstream event – the deterioration of the blood-brain barrier - may be a primary driver of neurodegeneration.
The BBB is a highly selective interface of cells that meticulously controls what enters and exits the brain. It’s the brain’s “guardian,” allowing essential nutrients while blocking harmful substances like bacteria and viruses. Increasingly, scientists recognize that BBB dysfunction is an early indicator of not only Alzheimer’s Disease, but also other neurological conditions like traumatic brain injury, stroke, and even age-related cognitive decline.
“We’ve historically underestimated the importance of the blood-brain barrier in neurodegenerative disease,” explains Dr. Andrew Pieper, co-lead researcher, psychiatrist, and neuroscientist at Case Western Reserve School of Medicine and Morley-Mather Chair of Neuropsychiatry at University Hospitals Cleveland Medical Center. “Our findings suggest that proactively protecting the BBB can effectively prevent the cascade of events leading to neurodegeneration and cognitive impairment.”
Targeting 15-PGDH: A Novel Enzyme and Therapeutic Pathway
the research team, co-led by Dr. Sanford Markowitz,Ingalls Professor of Cancer genetics and Distinguished University Professor at the Case Complete Cancer Center,identified a specific enzyme,15-hydroxyprostaglandin dehydrogenase (15-PGDH),as playing a crucial role in BBB breakdown. They discovered that 15-PGDH levels are significantly elevated in the BBB of individuals with Alzheimer’s Disease, those who have experienced traumatic brain injury, and even with normal aging – both in mouse models and human samples. This elevation appears to directly contribute to BBB dysfunction.
“We found that this enzyme is particularly enriched in the blood-brain barrier, and its increased activity correlates directly with damage to the barrier’s integrity,” states Dr. Markowitz. “This presented a clear and previously unexplored therapeutic target.”
SW033291: A Repurposed Drug with Remarkable Potential
Leveraging this finding, the researchers utilized a drug called SW033291, originally developed in Dr. Markowitz’s lab at Case Western Reserve and University Hospitals. Interestingly, SW033291 was initially designed to activate stem cells for tissue repair in conditions like colitis and bone-marrow transplants, with support from the Harrington Discovery Institute and Dean Stan Gerson. The team found that the drug effectively blocks the activity of 15-PGDH.
In mouse models of Alzheimer’s Disease,SW033291 demonstrated remarkable efficacy. The drug wholly preserved BBB integrity, preventing neurodegeneration and, crucially, maintaining cognitive and memory function. Importantly, the drug’s effect was self-reliant of amyloid levels, offering a distinct advantage over currently approved AD medications that primarily focus on amyloid removal – treatments that often yield limited clinical benefit and carry potential side effects.”The fact that SW033291 doesn’t directly target amyloid is significant,” Dr. Markowitz emphasizes. “It suggests a completely new mechanism for treating Alzheimer’s, one that addresses a fundamental underlying cause of the disease rather than just attempting to manage its symptoms.”
Beyond Alzheimer’s: Potential for Traumatic Brain Injury and Other Neurological Conditions
The benefits of SW033291 extend beyond Alzheimer’s Disease. The study also revealed that the drug protected mice from neurodegeneration and cognitive impairment after experiencing a traumatic brain injury,even when administered a full day post-injury – a timeframe relevant to real-world clinical scenarios. This suggests a potential therapeutic window for mitigating the long-term consequences of concussions and
