Astrocytes, an important class of supporting cells in the brain, are
thought to produce most of its cholesterol. 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.
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.
‘Mice that are genetically modified to suppress cholesterol production in the brain show dramatic symptoms of neurological damage. This helps explain the risk of developing Alzheimer's disease in diabetes.’
This finding may help to explain why the risk of developing
Alzheimer's disease increases in diabetes, says Heather Ferris, 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.
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
The results were striking. "Compared to normal animals, these mice
have very small brains, and multiple behavioral abnormalities," says
"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, 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
Curiously enough, the mice also displayed changes in their
whole-body metabolism, burning more carbohydrates and gaining less
"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,"
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."