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URMC / Research / Research@URMC / March 2017 / Protein Key to Nerve Health Hitches a Ride on Brain’s Garbage Truck

Protein Key to Nerve Health Hitches a Ride on Brain’s Garbage Truck

astrocytes and neuronsA new study shows that the brain’s waste removal system serves as both trash collector and delivery service, providing neurons with a protein important to maintaining cognitive function while simultaneously cleaning brain tissue.  The research may help explain why different genetic varieties of the protein, called apolipoprotein E (apoE), can indicate risk for Alzheimer’s disease or promote longevity.

The study was led by Rashid Deane, B.Sc., Ph.D., a research professor in the University of Rochester Medical Center Department of Neurosurgery and member of the Center for Translational Neuromedicine, and appears in the journal Molecular Neurodegeneration.

ApoE is responsible for delivering cholesterol to nerve cells in the brain and plays a key role in synaptic plasticity, the process by which neurons build new connections in order to learn and store memories.    

There are three different types of ApoE and the version present in our bodies is determined genetically.  ApoE3 is the most common and is found in approximately 78 percent of the population.  ApoE2 and apoE4 appear in 7 percent and 15 percent of the population, respectively, and these two variants have been associated with dementia.  ApoE2 appears to have neuro-protective qualities and individuals with this version of the protein are less likely to develop the disease.  However, individuals with apoE4 have a 12-fold risk of developing dementia. 

While apoE is present throughout our bodies, the source of the protein and its distribution is different in the brain, which maintains its own closed ecosystem.  In the brain, apoE is primarily created by astrocytes, an important support cell that is responsible for maintaining the health of neurons.  Another source is a structure deep within the brain called the choroid plexus.

Scientists speculate that the brain possesses two different sources of apoE because astrocytes, which are present throughout the brain and supply the protein to nearby neurons, may not be able to produce enough to meet demand.  The unanswered question, however, was how the additional protein gets from the choroid plexus to where it is needed in other parts of the brain. 

The new study, which was conducted in mice, indicates that the glymphatic system – which was first detailed by URMC researchers back in 2012 as a unique and self-contained waste removal system– plays a role in moving the extra apoE from the choroid plexus to the rest of the brain.  As the glymphatic system pumps cerebral spinal fluid (CSF) through brain tissue, not only does this process wash away waste, it simultaneously delivers apoE from the choroid plexus to nerve cells. 

The study may also shed light on why the different variants of apoE have an impact on dementia risk.  ApoE2, which is associated with lower Alzheimer’s risk, travels farther in the brain as it hitches a ride with the CSF and thereby benefits more neurons.   ApoE4, by contrast, only reaches a smaller number of nerve cells.  The researchers also noted that the distribution of apoE is impaired if the animals were sleep deprived, a finding that reinforces the link between lack of sleep and neurodegenerative diseases like Alzheimer’s.

Additional co-authors of the study include Thiyagarahan Achariyar, Baoman Li, Weiguo Peng, Evan McConnell, Abdellatif Benraiss, Tristan Kasper, Wei Song, Takahiro Takana, and Maiken Nedergaard with URMC and Phillip Verghese ,Yang Shi and David  M. Holtzman with Washington University.  The research was supported with funding from the National Institute of Neurological Disorders and Stroke.

Mark Michaud | 3/8/2017

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