Pericyte Degeneration Limits Brain’s Oxygen Supply

Abnormalities in pericytes, cells that wrap around cappillaries in the brain, lead to neuron deterioration, possibly affecting the development of Alzheimer’s disease, a study led by University of Southern California researchers reports.

Pericytes are “gatekeeper cells” that surround blood vessels. They contract and dilate to regulate blood flow to active parts of the brain, in turn regulating key neurovascular functions of the brain.

The study was the first to use a pericyte-deficient mouse model to test how blood flow is regulated in the brain. The team wanted to investigate whether pericytes could be an important new therapeutic target for treating neuron deterioration.

Ground Zero For Neurodegenerative Disorders?

Senior author Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC, said:

“Pericyte degeneration may be ground zero for neurodegenerative disorders like Alzheimer’s disease, ALS and possibly others. A glitch with gatekeeper cells that surround capillaries may restrict blood and oxygen supply to active areas of the brain, gradually causing neuron loss that might have important implications for Alzheimer’s disease.”

Kassandra Kisler, co-first author and a research associate at the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC, added:

“Vascular problems increase the risk of cognitive impairment in many types of dementia, including Alzheimer’s disease. Pericytes play an important part in keeping your brain healthy.”

Pericyte dysfunction suffocates the brain, leading to metabolic stress, accelerated neuronal damage and neuron loss, the researchers theorized. To test the hypothesis, researchers stimulated the hind limb of young mice deficient in gatekeeper cells and monitored the global and individual responses of brain capillaries, the smallest blood vessels in the brain.

The global cerebral blood flow response to an electric stimulus was reduced by about 30 percent compared to normal mice, denoting a weakened system.

Pericyte Degeneration Affects

Relative to the control group, the capillaries of pericyte-deficient mice took 6.5 seconds longer to dilate. Slower capillary widening and a slower flow of red blood cells carrying oxygen through capillaries means it takes longer for the brain to get its fuel.

As the mice turned 6 to 8 months old, global cerebral blood flow responses to stimuli progressively worsened. Blood flow responses for the experimental group were 58 percent lower than that of their age-matched peers.

In short, with age, the brain’s malfunctioning vascular system exponentially worsens.

Amy Nelson, co-first author and a postdoctoral scholar at the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC, said:

“We now understand the function of blood vessel gatekeeper cells is to ensure adequate oxygen and energy supply to brain cells. Prior to our study, scientists knew patients with Alzheimer’s disease, ALS and other neurodegenerative disorders experience changes to the blood flow and oxygen being supplied to the brain and that pericytes die. Our study adds a new piece of information: Loss of these gatekeeper cells leads to impaired blood flow and insufficient oxygen delivery to the brain.

The big mystery now is: What kills pericytes in Alzheimer’s disease?”

The research was supported by the National Institutes of Health; the National Natural Science Foundation of China; and the American Heart Association

Kassandra Kisler, Amy R Nelson, Sanket V Rege, Anita Ramanathan, Yaoming Wang, Ashim Ahuja, Divna Lazic, Philbert S Tsai, Zhen Zhao, Yi Zhou, David A Boas, Sava Sakadžić & Berislav V Zlokovic
Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain
Nature Neuroscience (2017) doi:10.1038/nn.4489

Image: Pericytes wrapped around capillaries in the cortex of a mouse brain. Credit: Amy Nelson/Keck School of Medicine of USC