Toxic fatty acids to blame for brain cell death after injury
Finding could advance treatment of glaucoma, Alzheimer's, and other brain diseases

Date:
October 6, 2021
Source:
NYU Langone Health / NYU Grossman School of Medicine
Summary:
Cells that normally nourish healthy brain cells called neurons
release toxic fatty acids after neurons are damaged, a new study in
rodents shows. This phenomenon is likely the driving factor behind
most, if not all, diseases that affect brain function, as well as
the natural breakdown of brain cells seen in aging, researchers say.



FULL STORY ========================================================================== Cells that normally nourish healthy brain cells called neurons release
toxic fatty acids after neurons are damaged, a new study in rodents
shows. This phenomenon is likely the driving factor behind most, if
not all, diseases that affect brain function, as well as the natural
breakdown of brain cells seen in aging, researchers say.


========================================================================== Previous research has pointed to astrocytes -- a star-shaped glial cell
of the central nervous system -- as the culprits behind cell death seen
in Parkinson's disease and dementia, among other neurodegenerative
diseases. While many experts believed that these cells released a neuron-killing molecule to "clear away" damaged brain cells, the identity
of this toxin has until now remained a mystery.

Led by researchers at NYU Grossman School of Medicine, the new
investigation provides what they say is the first evidence that tissue
damage prompts astrocytes to produce two kinds of fats, long-chain
saturated free fatty acids and phosphatidylcholines. These fats then
trigger cell death in damaged neurons, the electrically active cells
that send messages throughout nerve tissue.

Publishing Oct. 6 in the journal Nature, the study also showed that when researchers blocked fatty acid formation in mice, 75 percent of neurons survived compared with 10 percent when the fatty acids were allowed
to form.

The researchers' earlier work showed that brain cells continued to
function when shielded from astrocyte attacks.

"Our findings show that the toxic fatty acids produced by astrocytes play
a critical role in brain cell death and provide a promising new target for treating, and perhaps even preventing, many neurodegenerative diseases,"
says study co-senior author Shane Liddelow, PhD.

Liddelow, an assistant professor in the Department of Neuroscience
and Physiology at NYU Langone Health, adds that targeting these fats
instead of the cells that produce them may be a safer approach to treating neurodegenerative diseases because astrocytes feed nerve cells and clear
away their waste.

Stopping them from working altogether could interfere with healthy
brain function.

Although it remains unclear why astrocytes produce these toxins,
it is possible they evolved to destroy damaged cells before they
can harm their neighbors, says Liddelow. He notes that while healthy
cells are not harmed by the toxins, neurons become susceptible to the
damaging effects when they are injured, mutated, or infected by prions,
the contagious, misfolded proteins that play a major role in mad cow
disease and similar illnesses. Perhaps in chronic diseases like dementia,
this otherwise helpful process goes off track and becomes a problem,
the study authors say.

For the investigation, researchers analyzed the molecules released by astrocytes collected from rodents. They also genetically engineered some
groups of mice to prevent the normal production of the toxic fats and
looked to see whether neuron death occurred after an acute injury.

"Our results provide what is likely the most detailed molecular map to
date of how tissue damage leads to brain cell death, enabling researchers
to better understand why neurons die in all kinds of diseases," says
Liddelow, also an assistant professor in the Department of Ophthalmology
at NYU Langone.

Liddelow cautions that while the findings are promising, the genetic
techniques used to block the enzyme that produces toxic fatty acids
in mice are not ready for use in humans. As a result, the researchers
next plan is to explore safe and effective ways to interfere with the
release of the toxins in human patients. Liddelow and his colleagues had previously shown these neurotoxic astrocytes in the brains of patients
with Parkinson's, Huntington's disease, and multiple sclerosis, among
other diseases.

Funding for the study was provided by National Institutes of Health grants
P30 CA124435, S10 RR027425, UL1 TR002529, and P30 CA023168. Further
funding support was provided by the Cure Alzheimer's Fund, The Blas
Frangione Foundation, the U.S. Department of Defense, the Purdue
Integrative Data Science Institute award, the Stark Neurosciences Research Institute, the Indiana Alzheimer Disease Center, and Eli Lilly. Liddelow maintains a financial interest in AstronauTx Ltd, a company targeting astrocytes as a possible treatment target for Alzheimer's disease. The
terms and conditions are being managed in accordance with the policies
of NYU Langone.

In addition to Liddelow, other NYU Langone investigators involved in
the study included Philip Hasel, PhD, and Uriel Rufen-Blanchette. Other
study authors were first author Kevin Guttenplan, PhD; Maya Weigel,
BA; Aaron Gilter, PhD; and co-senior author Ben Barres, MD, PhD;
at Stanford University in Palo Alto, Calif.; Priya Prakash, PhD;
Prageeth Wijewardhane; Jonathan Fine, PhD; and Guarav Chopra, PhD,
at Purdue University in West Lafayette, Ind.; and Mikaela Neal, BS,
and Kimberley Bruce, PhD, at the University of Colorado in Aurora.

========================================================================== Story Source: Materials provided by NYU_Langone_Health_/_NYU_Grossman_School_of_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Guttenplan, K.A., Weigel, M.K., Prakash, P. et al. Neurotoxic
reactive
astrocytes induce cell death via saturated lipids. Nature, 2021
DOI: 10.1038/s41586-021-03960-y ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211006112617.htm

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