University of Southern California Grants More Than $16 Million to Research Vascular Dysfunction, Alzheimer’s Disease

NIH awards USC more than $16 million for research on vascular dysfunction and Alzheimer’s disease

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NIH awards USC more than $16 million for research into vascular dysfunction and Alzheimer’s disease

Research funded by the grant will benefit from the development of biomarkers and advanced imaging by scientists at USC’s Keck School of Medicine to launch studies that track changes in the blood-brain barrier, neurovascular function and cognition.

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The National Institute on Aging, a division of the National Institutes of Health, has Berislav Zlokovic, MD, PhD, director of the Zilkha Neurogenetic Institute, and Arthur W. Toga, PhD, director of the USC Mark and Mary Stevens Neuroimaging and Informatics Institute awarded (Stevens INI), $16.1 million to continue research into the role that blood vessel dysfunction plays in the development of dementia and Alzheimer’s disease.

“There is mounting evidence that neurovasculature plays an important role in early cognitive decline,” said Zlokovic, chair and professor of physiology and neuroscience at USC’s Keck School of Medicine. “This grant allows us to advance important research into how changes in the blood-brain barrier and blood flow interact with amyloid-beta and tau pathology to induce structural and functional changes in the brain, leading to cognitive impairment and early Alzheimer’s disease.”

More than 30 years ago, Zlokovic was one of the first to suggest that defects in the blood-brain barrier, which prevents harmful substances in the blood from reaching brain tissue, could be the early, underlying cause of most cognitive impairments. rather than the accumulation of amyloid beta plaque, which had long been the focus of Alzheimer’s research. With this award, he and his colleagues can further test this so-called neurovascular hypothesis.

“This work builds on our previous work, which has shown that humans can develop mild cognitive impairment independent of amyloid beta and tau if the blood-brain barrier is damaged,” Zlokovic said.

Documenting the progression of Alzheimer’s disease

With the funding, the team of researchers can initiate longitudinal studies comparing the progress of more than 400 people with a genetic variant that puts them at high risk of developing Alzheimer’s disease – known as apolipoprotein E4 (APOE4) – with more than 450 people with APOE3 , another variant that puts them at a lower risk of developing Alzheimer’s disease.

About 75% of the participants will be cognitively unaffected at the start of the study and about 25% will have only mild impairment. The researchers will follow them for five years, monitoring changes in the blood-brain barrier, blood flow, and brain structure and function, while monitoring participants for cognitive impairment, using neuroimaging and molecular biomarkers that indicate blood vessel dysfunction. developed by Zlokovic, and advanced brain imaging technology developed by Toga.

“Using our ultra-high field 7T magnetic resonance imaging (MRI) scanner has transformed our understanding of how fluid-filled regions in the brain – perivascular spaces – affect brain health. Here at Stevens INI, we have this advanced imaging successfully used to enable breakthroughs, including the central role that the perivascular space plays in brain changes associated with aging, including neurodegenerative disorders,” said Toga, provost professor of ophthalmology, neurology, psychiatry and the Behavioral Sciences, Radiology and Engineering. the Keck School of Medicine.”Our imaging capabilities have enabled us to conduct a multimodal assessment of the role of neurovasculature in cognitive decline, an extensive program of research into perivascular spaces, and numerous close-up studies of how fluids travel through the brain, including through the white ood brain barrier . I am delighted to have received this funding to continue our work in partnership with Dr. Zlokovic to continue.”

Researchers hope the work will lead to a better understanding of the onset and progression of Alzheimer’s disease and the identification of the best interventions for different stages of the disease.

Testing treatments in the lab

At the same time, the team will conduct additional lab studies using mice genetically modified to carry human APOE gene variants to document changes in the brain that lead to cognitive decline and to test a potential treatment.

The treatment is an experimental neuroprotective enzyme co-developed by Zlokovic’s team, in collaboration with John Griffin, PhD, of the Scripps Research Institute, called 3K3A-APC, an engineered form of human-activated protein C. Researchers will test it in the altered mice to see if it can protect the integrity of the blood-brain barrier and prevent cognitive decline. In addition, they hope to investigate whether this type of intervention is effective at the earliest signs of vascular dysfunction or at later stages of disease in mouse models that also have amyloid beta and tau. The National Institute of Neurological Disorders and Stroke (NINDS) recently awarded funding for a pivotal Phase 3 clinical trial of 3K3A-APC in stroke patients, led by Patrick Lyden, MD, professor of physiology and neuroscience at the Zilkha Neurogenetic Institute.

“We hope that the results of this study will eventually lead us to new treatments for people with the APOE4 gene,” Zlokovic says.

Turning biomarkers into a blood test for Alzheimer’s disease

Zlokovic added that they are continuing to improve on key molecular biomarkers, and he hopes eventually to discover biomarkers that are detectable in blood, which would make identifying people at risk for Alzheimer’s disease easier and more accessible.

“We have followed different directions of research that all complement each other,” says Zlokovic. “We believe this research will contribute to important new findings on the pathogenesis of cognitive decline and also lead to the development of important new therapies for cognitive impairment, dementia and Alzheimer’s disease.”

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