Stroke drug treats mouse model of Alzheimer’s disease
March 08, 2019
LA JOLLA, CA — For the last decade, Scripps Research professor John Griffin, PhD, has been developing and testing a drug candidate that eases inflammation and protects brain cells and blood vessels from damage. Prior research had shown that the drug, 3K3A-activated protein C (3K3A-APC), improves the outcome of mice with stroke and acute brain injuries. Now, research by Griffin and his collaborators shows another potential application: treating Alzheimer’s disease. In a mouse model of Alzheimer’s, 3K3A-APC prevented amyloid plaques from accumulating in the brain and improved the mice’s symptoms.
“This adds to the list of pathologies for which 3K3A-APC is surprisingly beneficial,” says Griffin a professor of molecular medicine at Scripps Research. “The data support the idea that this is a potential therapy for early-stage Alzheimer’s in humans.”
In all humans, activated protein C (APC) is found in the blood, where it both stops blood from clotting and sends anti-inflammatory signals to cells throughout the body. Griffin’s team discovered that changing just three amino acids in the protein kept it from affecting clotting while still retaining its signaling ability. The resulting protein, 3K3A-APC, lowers levels of inflammation in the brain, keeps neurons from dying, and maintains the health of blood vessels. Last year, a Phase 2 clinical trial showed that the drug reduced hemorrhaging in stroke patients and in January, final results of that trial were published, confirming its safety and benefit. Preclinical studies have also shown benefit in multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS).
Griffin and his long-time collaborator Berislav Zlokovic, MD, PhD, of the University of Southern California, Los Angeles, wondered whether 3K3A-APC might also work to protect neurons in the brains of people with Alzheimer’s disease.
“The drug is neuroprotective by multiple mechanisms. Moreover, in different types of cells, it can affect the expression of more than 500 genes,” says Griffin. “You never know if it’s going to be beneficial in different scenarios until you try it.”
So, Griffin provided Zlokovic’s lab with the 3K3A-APC, and the researchers began giving daily treatments of the drug to mice with genetic mutations that make them develop a mouse version of Alzheimer’s disease. In the mice, as in humans, accumulation of the protein amyloid-β into amyloid plaques is associated with the symptoms and progression of Alzheimer’s. The animals used in the study, called 5XFAD mice, usually begin accumulating amyloid-β by two months of age and showing memory deficits a month or two later.
The team reported in the Journal of Experimental Medicine that four months of daily treatment with 3K3A-APC, starting when the 5XFAD mice were three months old, reduced the accumulation of amyloid-β in the mice’s brains by nearly half and lowered levels of inflammatory molecules. Moreover, at the end of the study period, the treated 5XFAD mice performed as well as healthy control mice in memory tests. The researchers went on to show that the drug worked by blocking another protein, BACE1, which normally plays a role in the generation of amyloid- β.
“What’s exciting is that this drug, which is a slightly modified normal human blood protein, has already been shown to be safe in humans in our stroke trials,” says Griffin. However, more research will be needed, he adds, to see if the results in mice hold up in humans with Alzheimer’s disease. Griffin and Zlokovic also plan to test 3K3A-APC in other neurodegenerative brain diseases.
In addition to Griffin and Zlokovic, authors of the study, “3K3A-activated protein C blocks amyloidogenic BACE1 pathway and improves functional outcome in mice,” are Divina Lazic, Abhay Sagare, and Angeliki Nikolakopoulou of the University of Southern California and Robert Vassar of Northwestern University.
This work was supported by funding from by the National Institutes of Health (grants NS090904 and HL052246) and by University of Southern California start-up funds. B.V. Zlokovic is a scientific founder and chairs the scientific advisory board of ZZ Biotech LLC, a biotechnology company with a mission to develop APC and its functional mutants for the treatment of stroke and other neurological disorders. J.H. Griffin is a consultant for ZZ Biotech LLC.
For more information, contact press@scripps.edu