Neuroprotective mechanism altered by Alzheimer's disease risk genes


Date:
January 3, 2022
Source:
Baylor College of Medicine
Summary:
Researchers have discovered that gene variants associated with
risk of developing Alzheimer's disease disturb the brain's natural
protective mechanism against the condition.



FULL STORY ==========================================================================
The brain has a natural protective mechanism against Alzheimer's disease,
and researchers at Baylor College of Medicine, Texas Children's Hospital
and collaborating institutions have discovered that gene variants
associated with risk of developing the disease disturb the protective
mechanism in ways that can lead to neurodegeneration. The researchers
also showed in a fruit fly model of the condition that a chemical known
as ABCA1 agonist can restore certain alterations of the brain protective mechanism.


==========================================================================
The team reveals evidence supporting reactive oxygen species (ROS),
natural byproducts of cellular metabolism linked to inflammation and
other processes, as key players in events leading to the disruption of the neuroprotective mechanism. In addition, the researchers found that ROS, together with amyloid- beta, the main component in the plaques found
in the brains of people with Alzheimer's disease, accelerated disease development in animal models.

Altogether, the findings provide new mechanistic insight into factors
involved in Alzheimer's disease development, supporting the idea that
multiple alterations at the genetic and other cellular levels combine to
induce the disease. The study appears in the Proceedings of the National Academy of Sciences.

"Previous work conducted by Dr. Lucy Liu in Dr. Hugo Bellen's lab
and colleagues showed that two brain cell types, neurons and glia,
work together to protect against neurodegeneration," said first author
Dr. Matthew Moulton, a postdoctoral associate in the Bellen lab. "In the current study, we worked with fruit fly and mammal models to investigate whether known genetic risk factors for Alzheimer's disease were associated
with disturbing the protective mechanism, diving deep into the details
of how this happened." The neuroprotective mechanism is engaged when
neurons face high levels of ROS, which stimulates neurons to produce
abundant lipids. ROS levels increase with aging, different forms of
stress or because of genetic factors. The combination of ROS and lipids produces peroxidated lipids, which deteriorate cellular health. Neurons
try to avoid the 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,
thus keeping them from damaging neurons.

In the previous work, the researchers connected the neuroprotective
mechanism to the strongest genetic risk factor for Alzheimer's disease, apolipoprotein APOE4. "We found that APOE4 is practically unable to
transfer lipids to glia, while other two forms of APOE, APOE2 and APOE3,
carry out the transfer effectively," said Bellen, Distinguished Service Professor of molecular and human genetics at Baylor. "With APOE4, lipid
droplet accumulation in glia is drastically reduced and the protective mechanism breaks down. This fundamental difference in the function in
APOE4 likely primes an individual to be more susceptible to the damaging effects of ROS, which becomes elevated with age." "In the current work,
we wanted to identify genes that are critical for lipid droplet formation, specifically genes that are required for lipid export from neurons and
lipid import into glia," Moulton said. "We looked at genes that interact
with APOE in neurons to get the lipids out, and also in glia to get the
lipids in. One reason we are interested in this comes from human studies
that show that genes involved in both import and export of lipids have
been implicated in Alzheimer's disease and other related conditions."
The team investigated the role of these Alzheimer's risk genes in a fruit
fly model, one gene at a time. The model allowed them to visualize, in
the presence or absence of ROS, the effect of knocking down a particular
gene, either in neurons or in glia, on the formation of lipid droplets,
as well as on neurodegeneration.



==========================================================================
"In all cases in which ROS was present and we saw droplet loss, we
also saw neurodegeneration, again supporting that perturbations in glia
droplet formation can lead to neuronal damage," Moulton said.

With this approach, the team demonstrated that several genes that genome
wide sequencing studies had associated with risk of developing Alzheimer's disease disturbed neuroprotective lipid droplet formation, providing a mechanism that can explain the risk associated with these genes.

In addition, using the fruit fly model, Moulton and his colleagues tested whether an ABCA1 agonist, which was previously shown to restore APOE4's
ability to transfer lipids, could enable APOE4 to mediate lipid droplet formation in glia in the fruit fly model. "The ABCA1 agonist restored
glial lipid droplet formation in an APOE4 fruit fly model, highlighting
a potentially therapeutic avenue to prevent ROS-induced neurotoxicity,"
said Bellen, Chair in Neurogenetics in the Jan and Dan Duncan Neurological Research Institute at Texas Children's.

The researchers also investigated whether ROS could exacerbate the
effect amyloid-beta may have on the disease. "We observed that ROS and amyloid-beta together increased neuronal death in fruit flies and resulted
in larger and more numerous amyloid-beta-rich plaques in a mouse model, suggesting that, indeed, ROS and amyloid-beta can interact and potentially influence disease progression," Moulton said.

"As we age, ROS in the brain increases. If in addition there are
mutations that disrupt the droplet pathways, then neurons can become
sensitive to the accumulation of lipid droplets and this can pave
the way to neurodegeneration," Bellen said. "Our findings support
further investigations into feasible means to reduce the levels of
ROS in the brain as a strategy to minimize ROS's key contribution
to neurodegeneration." Other contributors to this work include Scott
Barish, Isha Ralhan, Jinlan Chang, Lindsey D. Goodman, Jake G. Harland,
Paul C. Marcogliese, Jan O.

Johansson and Maria S. Ioannou. The authors are affiliated with one or
more of the following institutions: Baylor College of Medicine, Jan and
Dan Duncan Neurological Research Institute at Texas Children's Hospital, University of Alberta, Neuroscience and Mental Health Institute, Alberta
and Artery Therapeutics, Inc.

Support for this work was provided by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes
of Health (NIH) award number P50HD103555, NIH award number U54HD083092,
grants from the Texas Alzheimer's Research and Care Consortium under
award number 2018-497 05-11-II and from The National Institute on Aging
of NIH, award number R01498 AG073260. Further support was provided by the Medical Genetics Research Fellowship Training Grant (NIH award number T32 GM07526-41), the Brain Disorders & Development Fellowship Training Grant
(NIH award number T32501 NS043124-18), grants from Canadian Institutes of Health Research (MFE-64712, 173321) and the Heart & Stroke Foundation of
Canada (award number 170722.) In addition, support was provided by Alberta Synergies in Alzheimer's and Related Disorders (SynAD) program funded
by the Alzheimer Society of Alberta and Northwest Territories through
its Hope for Tomorrow program and the University Hospital Foundation,
the Neuroscience and Mental Health Institute at the University of Alberta
and the Howard Hughes Medical Institute.

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Content may be edited for style and length.


========================================================================== Journal Reference:
1. Matthew J. Moulton, Scott Barish, Isha Ralhan, Jinlan Chang,
Lindsey D.

Goodman, Jake G. Harland, Paul C. Marcogliese, Jan O. Johansson,
Maria S.

Ioannou, Hugo J. Bellen. Neuronal ROS-induced glial lipid droplet
formation is altered by loss of Alzheimer's disease-associated
genes.

Proceedings of the National Academy of Sciences, 2021; 118 (52):
e2112095118 DOI: 10.1073/pnas.2112095118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220103121721.htm
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