Neutrophils Reduce Cerebral Blood Flow in Mouse Model of Alzheimer's
Optical section of a whole mouse brain. Blood vessels are stained. Stitched images were acquired using a custom made light sheet fluorescence microscope. Image credit: Antonino Paolo Di Giovanna, Ludovico Silvestri, Marie Caroline Muellenbroich via Wikipedia Commons
You know that dizzy feeling you get when, after lying down for an extended period, you stand up a little too quickly?
That feeling is caused by a sudden reduction of blood flow to the brain, a reduction of around 30 percent. Now imagine living every minute of every day with that level of decreased blood flow.
People with Alzheimer’s disease don’t have to imagine it. The existence of cerebral blood flow reduction in Alzheimer’s patients has been known for decades, but the exact correlation to impaired cognitive function is less understood.
“People probably adapt to the decreased blood flow, so that they don’t feel dizzy all of the time, but there’s clear evidence that it impacts cognitive function,” said Chris Schaffer, associate professor in the Meinig School of Biomedical Engineering.
A new study from the joint lab of Schaffer and Nozomi Nishimura, associate professor in the Meinig School, offers an explanation for this dramatic blood flow decrease: white blood cells stuck to the inside of capillaries, the smallest blood vessels in the brain. And while only a small percentage of capillaries experience this blockage, each stalled vessel leads to decreased blood flow in multiple downstream vessels, magnifying the impact on overall brain blood flow.
Their paper, “Neutrophil Adhesion in Brain Capillaries Reduces Cortical Blood Flow and Impairs Memory Function in Alzheimer’s Disease Mouse Models,” published Feb. 11 in Nature Neuroscience. It was also among a select group of papers highlighted at the Society for Neuroscience annual meeting, held Nov. 3-7, 2018, in San Diego.
The paper’s co-lead authors are Jean Cruz-Hernandez, Ph.D. ’17, now a postdoctoral researcher at Harvard Medical School, and Oliver Bracko, a research associate in the Schaffer-Nishimura Lab.
The paper, Schaffer said, is the culmination of approximately a decade of study, data gathering and analysis. It began with a study in which Nozomi was attempting to put clots into the vasculatures of Alzheimer’s mouse brains to see their effect.
“It turns out that … the blockages we were trying to induce were already in there,” she said. “It sort of turned the research around – this is a phenomenon that was already happening.”
The researchers, including then-undergraduate Joan Zhou ‘08, M.Eng. ‘09, determined that only about 2 percent of brain capillaries had “stalls” (blockages), but the cumulative effect of that small number of stalls was an approximately 20 percent overall decrease in brain blood flow, due to the slowing of downstream vessels by the capillaries that were stalled. Recent studies suggest that brain blood flow deficits are one of the earliest detectable symptoms of dementia.
To test the effect of the stalls on performance of memory tasks in Alzheimer’s mice, they were given an antibody that interfered with the adhesion of white blood cells to capillary walls, which caused the stalled capillaries to start flowing again and thus increased overall brain blood flow. Memory function was improved within a few hours, even in aged mice with more advanced stages of Alzheimer’s disease.
Schaffer and Nishimura are quick to point out, however, that the antibody is not something that can be used in humans. Also, of course, interfering with white blood cell adhesion would render an individual immunocompromised.
“What we’ve done is identify the cellular mechanism that causes reduced brain blood flow in Alzheimer’s disease models, which is neutrophils [white blood cells] sticking in capillaries,” Schaffer said. “We’ve shown that when we block the cellular mechanism [that causes the stalls], we get an improved blood flow, and associated with that improved blood flow is immediate restoration of cognitive performance of spatial- and working-memory tasks.”
“Now that we know the cellular mechanism,” he said, “it’s a much narrower path to identify the drug or the therapeutic approach to treat it.”
The team has identified approximately 20 drugs, many of them already FDA approved for human use, that have potential in dementia therapy. Some of them, however, were designed to be taken in high doses for short periods of time to treat sepsis, or in the immediate aftermath of a heart attack or stroke. “They weren’t really intended to be something that you take for the rest of your life,” Schaffer said. Nonetheless, the lab is screening these drugs in Alzheimer’s mice now.
Schaffer said he’s “super-optimistic” that, if the same capillary-blocking mechanism is at play in humans as it is in mice, this line of research “could be a complete game-changer for people with Alzheimer’s disease.”
Other contributors included Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine; Laibaik Park, associate professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine; doctoral student Mohammad Haft-Javaherian; and numerous former undergraduate and graduate students of the Schaffer-Nishimura Lab.
This research was funded by the National Institutes of Health, the Alzheimer’s Drug Discovery Foundation, the Alzheimer’s Art Quilt Initiative, and the Brightfocus Foundation.
This article has been republished from materials provided by Cornell University. Note: material may have been edited for length and content. For further information, please contact the cited source.
Hernández, J. C., Bracko, O., Kersbergen, C. J., Muse, V., Haft-Javaherian, M., Berg, M., . . . Schaffer, C. B. (2019). Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nature Neuroscience. doi:10.1038/s41593-018-0329-4
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