A deficiency in the protein responsible for moving glucose across the brain’s protective blood-brain barrier appears to intensify the effects of Alzheimer’s disease, according to a new study from the Keck School of Medicine of USC.
The research suggests that targeting the protein called GLUT1 could help prevent or slow the effects of Alzheimer’s, especially among those at risk for the disease. The study appeared March 2 in the online edition of the scientific journal Nature Neuroscience.
“Our results suggest that GLUT1 deficiencies at the blood-brain barrier are not just symptoms of Alzheimer’s but, in fact, lead to a series of vascular injuries that worsen the effects of the disease,” said the study’s principal investigator, Berislav V. Zlokovic, MD, PhD, who is director of the Zilkha Neurogenetic Institute at the Keck School and the Mary Hayley and Selim Zilkha Chair for Alzheimer’s Disease. “We do not know yet whether medicine can restore GLUT1 expression, but we believe that targeting the protein may help prevent Alzheimer’s from getting worse among individuals predisposed to develop the disease.”
About 5.2 million people of all ages in the United States have Alzheimer’s disease, an irreversible, progressive brain disease that causes problems with memory, thinking and behavior. According to the Alzheimer’s Association, it is the most common type of dementia, a general term for loss of memory and other mental abilities. Alzheimer’s is projected to affect 16 million Americans over age 65 by 2050.
Glucose is the brain’s main energy source, and GLUT1 helps move it across the blood-brain barrier, a cellular layer that prevents entry of blood and pathogens into the brain. Previous research has shown diminished glucose uptake in the brain among individuals at genetic risk for Alzheimer’s disease, as well as those with a positive family history who develop the disease but show mild or no cognitive impairment.
In this new study, Zlokovic’s team used transgenic mice to show that GLUT1 is necessary to maintain proper brain capillary networks, blood flow and blood-brain barrier integrity. They found that GLUT1 deficiency led to diminished glucose uptake into the brain as early as two weeks of age and, by six months of age, neuronal dysfunction, behavioral deficits, elevated levels of amyloid-beta peptide, behavioral changes and neurodegenerative changes.
The team also found that GLUT1 deficiency in the endothelium – the inner lining of blood vessels – initiated breakdown of the blood-brain barrier. Alzheimer’s disease pathogenesis is widely believed to be driven by amyloid-beta peptide buildup in the brain, which is facilitated by a breakdown of the blood-brain barrier.
Other USC co-authors include Ethan A. Winkler, Abhay P. Sagare, Sanket V. Rege, Jesse D. Sengillo, Pan Kong, Amy R. Nelson, John S. Sullivan, Zhen Zhao, Herbert J. Meiselman, Rosalinda B. Wenby, Jacob Makshanoff and Edward Zuniga.
— Alison Trinidad