Targeting vascular activation to treat Alzheimer’s disease: an interview with Paula Grammas
In this interview, Paula Grammas, Executive Director, describes recent investigations into under-explored therapeutic targets for Alzheimer’s disease at the George & Anne Ryan Institute for Neuroscience.
As part of our monthly focus on neurodegenerative drug development, we spoke to Paula Grammas, Executive Director at the George & Anne Ryan Institute for Neuroscience (RI, USA), to learn more about her current research and her predictions for the future.
Please could you introduce yourself?
I am the Executive Director of the George & Anne Ryan Institute for Neuroscience at the University of Rhode Island (URI). The George & Anne Ryan Institute was created in 2013 to fill a niche in investigating under-explored therapeutic targets in neurodegenerative disease. Our faculty includes approximately 40 researchers and clinicians from URI and the state of Rhode Island who are committed to integrating discovery science, translational medicine and community outreach in the fight against these diseases. We have a particular focus on the role of inflammation, the immune system and vascular factors in neurodegeneration.
Prior to coming to URI, I was at the Texas Tech University Health Sciences Center (TX, USA), where I was the inaugural director of the Garrison Institute on Aging. Having moved from the biggest U.S. state to the smallest, I was struck by the uniquely close-knit and collaborative network of scientific talent in Rhode Island. It makes for an exciting neuroscience hub.
What is the focus of your current research?
Our research builds on the work we’ve done over the past 30 years investigating the role of cerebral vasculature in the pathogenesis of Alzheimer’s disease (AD). Our laboratory was the first to posit the idea that cerebral endothelial cells are pathologically activated in Alzheimer’s and that this activation contributes to neuronal cell death.
Our current work is progressing on two different but complementary paths. Our basic science laboratory continues to explore how altered cerebral endothelial function contributes to the death of neurons. We are investigating how cardiovascular risk factors, such as hypertension and diabetes, alter endothelial function and lead to vascular activation.
We are also attempting to dissect how brain endothelial cells can interact with other non-neuronal cells, such as microglia and astrocytes, to affect neuronal function and viability. Our second focus is to translate our basic science work into clinical trials. We will shortly be testing the idea that vascular activation is a target for Alzheimer therapeutics. We are very excited to partner with our clinician colleagues in Rhode Island to test this novel hypothesis.
How did you begin working in Alzheimer’s disease?
I was earning my doctorate degree in pathology when I first became curious about the role of the blood vessels in Alzheimer’s disease. In neurodegeneration it seemed like common sense to investigate the environment where nerve cells sit, but there was almost no one looking into cerebral vasculature as a functionally active participant in the pathogenesis of Alzheimer’s.
Please can you provide a quick summary of the recent paper you were involved in, ‘A new paradigm for the treatment of Alzheimer’s disease: targeting vascular activation’?
Our research has shown that the cerebral vasculature in patients with Alzheimer’s disease is pathologically activated to produce inflammatory proteins and neurotoxins. We hypothesized that this pathological process contributes to neuronal cell death and cognitive impairment in Alzheimer’s disease.
In 2014, we published work showing that the inhibition of this vascular activation leads to diminished production of noxious inflammatory and neurotoxic proteins from the cerebral vasculature of AD mice and, importantly, that this also improved their cognitive performance. Based on that study, in which we used the cancer-therapy drug sunitinib, we have extended this work with another drug that targets a key mediator of cerebrovascular activation: the multifunctional inflammatory protein thrombin. The results in animal models suggest that thrombin is a potentially disease-modifying therapeutic target in Alzheimer’s disease.
Where do you think the biggest breakthrough for this disease will come from?
I don’t think there will be one big breakthrough. I believe breakthroughs in this disease will come from multiple contributions in different fields. There is an increased understanding that Alzheimer’s is not a single disease but multiple pathologies with a common clinical presentation. More powerful imaging and better biomarkers will also make a difference in our ability to diagnose and treat the disease.
Where do you think the field of Alzheimer’s disease research will be in 10 years’ time?
Again, I think we will see acceptance of the fact that it is a multifactorial disease. This change in the way we think about Alzheimer’s will help us to develop a more sophisticated approach to therapy. As with HIV, it is likely patients will receive a cocktail of therapeutic interventions instead of one magic bullet. We also know that 40% of dementias are preventable and that lifestyle choices, especially in midlife, can impact the development of late-life dementias, including Alzheimer’s. I am hopeful that ten years from now, people will know they can take a proactive role in preventing or stalling neurodegenerative disease.
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