Impairing a critical partnership between brain cells can lead to
neurodegeneration. The study published in
reports a mechanism by which, normally support each other's functions.
‘Mutations that lead to a breakdown of the support system between neurons and glia can pave the way to neurodegeneration and free radicals are at the root of a key aspect of this process.’
The researchers discovered that when this mechanism fails, neurodegeneration
follows, opening a path to a better understanding of disorders such as
First author Dr. Lucy Liu, a Ph.D. graduate in neuroscience from the Bellen
lab, discovered in 2015 that a number of genes involved in
neurodegeneration promote damage to neurons and glia by inducing high levels of
free radicals (oxidative stress) and accumulation of lipid droplets in glia
This work sets the stage for the current study.
"Using electron microscopy, we observed lipid droplet accumulation in
glia before obvious symptoms of neurodegeneration," Liu said.
"In the presence of high levels
of oxidative stress, neurons produce an overabundance of lipids. The
combination of free radicals and lipids, which produces peroxidated lipids, is
detrimental to cellular health. Neurons try to avoid this damage by secreting
these lipids, and apolipoproteins - proteins that transport lipids - carry them
to glia cells. Glia store the lipids in lipid droplets, sequestering them from
the environment and providing a protective mechanism."
Liu and her colleagues discovered that the storage of lipid droplets in glia
protects neurons from damage as long as the free radicals do not destroy the
lipid droplets. When the lipid droplets are destroyed, cell damage and
Connection to Alzheimer's disease
"Our research brought us to a fascinating and unexpected finding,"
Liu said. "Approximately 15 percent of the human population carries
apolipoprotein APOE4. Since APOE4 was first linked to Alzheimer's disease
almost 30 years ago, it remains the strongest known genetic risk factor for
this disease. Meanwhile, APOE2, which is slightly different from APOE4, is
protective against the disease. This evidence suggests that APOE is important
for proper brain function, but we know little about how APOE itself may lead to
The researchers found that apolipoproteins APOE2, APOE3 and APOE4 have
different abilities to transfer lipids from neurons to glia and hence differ in
their ability to mediate the accumulation of lipid droplets.
"APOE2 and APOE3 can effectively transfer lipids into glia," Liu
On the other hand, APOE4 is practically unable to carry out this process.
This results in a lack of lipid droplet accumulation in glia and breakdown of
the protective mechanism that sequesters peroxidated lipids. This fundamental
difference in the function in APOE4 likely primes an individual to be more
susceptible to the damaging effects of oxidative stress, which becomes elevated
"Another contribution of this study is that glia play an important
protective role against oxidative stress in neurodegeneration," Bellen