Mice modified to produce less cholesterol in the brain suffer significant neurological damage.

BOSTON – (January 19, 2017) – Healthy brains need plenty of cholesterol for nerve cells to grow and work properly, but diabetes can reduce the amount of cholesterol in the brain, as a Joslin Diabetes Center team has demonstrated. Joslin researchers and their colleagues now have gone on to show that mice that are genetically modified to suppress cholesterol production in the brain show dramatic symptoms of neurological impairment. 

This finding may help to explain why the risk of developing Alzheimer’s disease increases in diabetes, says Heather Ferris, M.D., Ph.D., a Joslin research associate and lead author on a paper about the work published in PNAS.  

Scientists have long studied the roles of brain cholesterol in Alzheimer’s, one reason being that mutations in a cholesterol-carrying protein known as APOE are the strongest genetic risk factor for the disease, Ferris points out.

Astrocytes, an important class of supporting cells in the brain, are thought to produce most of its cholesterol. In their latest study, the Joslin researchers created a mouse model in which a gene known as SREBP2, the master regulator of cholesterol synthesis, has been knocked out.

The results were striking. “Compared to normal animals, these mice have very small brains, and multiple behavioral abnormalities,” says Ferris.

“Not only do these mice have trouble learning and remembering, they can’t perform some other normal daily behaviors such as building a nest,” adds C. Ronald Kahn, M.D., senior author on the paper, Joslin’s chief academic officer and the Mary K. Iacocca Professor of Medicine at Harvard Medical School. “Some of these effects were a little bit like Alzheimer’s disease in the mouse, except that they were much more severe.”

Curiously enough, the mice also displayed changes in their whole-body metabolism, burning more carbohydrates and gaining less weight.

“We’re only at the beginning of this research on how diabetes and Alzheimer’s disease could be related, but cholesterol could be a mediator,” says Ferris. While investigators in other labs have suggested that raised rather than lower levels of cholesterol may be linked to brain disorders, “we think our model may be more clinically relevant,” she says. 

Drugs that reduce cholesterol levels in the cardiovascular system can strongly benefit people with diabetes or related conditions, but cholesterol in the blood generally can’t cross into the brain, and cholesterol metabolism is quite different in the brain, she points out.

Going forward, the researchers are creating mouse models that will combine the lowered-brain-cholesterol model with models of Alzheimer’s disease or type 1 diabetes or type 2 diabetes. The scientists also will look at the effects of brain cholesterol deprivation in adult mice, in addition to mice born with the modification.

“This work gives another example of how research in one field of biomedicine can affect knowledge in another field,” Kahn comments. “We didn’t start out thinking about Alzheimer’s disease; we were trying to understand the effects of diabetes in the brain.” 

The paper’s other authors included Rachel Perry, Gabriela Moreira and Gerald Shulman from Yale University and Jay Horton from the University of Texas Southwestern. Lead funding was from the National Institute of Diabetes, Digestive and Kidney Diseases.

* * * 

Related Articles

A Scientist working in lab
Type 1
Kidney Disease
Research Highlights

The Preventing Early Renal Loss in Diabetes (PERL) Study Conclusion

The Preventing Early Renal Loss in Diabetes (PERL) Study Conclusion

Three-year clinical trial finds reducing uric acid levels in type 1 diabetes provides no beneficial impact on the progression of diabetic kidney disease BOSTON – (November 8, 2019) – Diabetic kidney...
Read more on The Preventing Early Renal Loss in Diabetes (PERL) Study Conclusion
National Diabetes Month
Type 1
Type 2

National Diabetes Awareness Month

National Diabetes Awareness Month

Diabetes is growing at an epidemic rate in the United States and across the globe. According to the Centers for Disease Control and Prevention (CDC), over 30 million Americans have diabetes and 1.5...
Read more on National Diabetes Awareness Month
Red blood cell traveling in an artery
Type 1
Heart Disease
Research Highlights

Research may show way to minimize complications after heart treatment

Research may show way to minimize complications after heart treatment

BOSTON – (October 1, 2019) – People with diabetes are much more likely to develop heart disease than those without the condition. They also are several times more likely to develop complications after...
Read more on Research may show way to minimize complications after heart treatment