Cholesterol drives Alzheimer's plaque formation

Date:
September 14, 2021
Source:
University of Virginia Health System
Summary:
The new findings offer important insights into how and why the
plaques form and may explain why genes associated with cholesterol
have been linked to increased risk for Alzheimer's.



FULL STORY ========================================================================== Cholesterol manufactured in the brain appears to play a key role in the development of Alzheimer's disease, new research indicates.


========================================================================== Scientists from the University of Virginia School of Medicine and their collaborators found that cholesterol produced by cells called astrocytes
is required for controlling the production of amyloid beta, a sticky
protein that builds up in the brains of patients with Alzheimer's. The
protein accumulates into insoluble plaques that are a hallmark of the
disease. Many efforts have targeted these plaques in the hope that
removing or preventing them could treat or prevent Alzheimer's.

The new findings offer important insights into how and why the plaques
form and may explain why genes associated with cholesterol have been
linked to increased risk for Alzheimer's. The results also provide
scientists with important direction as they seek to prevent Alzheimer's.

"This study helps us to understand why genes linked to cholesterol are so important to the development of Alzheimer's disease," said researcher
Heather A. Ferris, MD, PhD, of UVA's Division of Endocrinology and
Metabolism. "Our data point to the importance of focusing on the
production of cholesterol in astrocytes and the transport to neurons as
a way to reduce amyloid beta and prevent plaques from ever being formed." Alzheimer's Plaques and Cholesterol While cholesterol is often associated
with clogged arteries and heart disease, it plays important roles in
the healthy body. The body makes cholesterol naturally so it can produce hormones and carry out other important functions.

The new discovery from Ferris and her collaborators adds a new entry to cholesterol's list of responsibilities.

The work also sheds light on the role of astrocytes in Alzheimer's
disease.

Scientists have known that these common brain cells undergo dramatic
changes in Alzheimer's, but they have been uncertain if the cells were suffering from the disease or contributing to it. The new results suggest
the latter.

The scientists found that astrocytes help drive the progression of
Alzheimer's by making and distributing cholesterol to brain cells called neurons. This cholesterol buildup increases amyloid beta production and,
in turn, fuels plaque accumulation.

Normally, cholesterol is kept quite low in neurons, limiting the buildup
of amyloid beta. But in Alzheimer's, the neurons lose their ability to
regulate amyloid beta, resulting in plaque formation.

Blocking the astrocytes' cholesterol manufacturing "robustly" decreased
amyloid beta production in lab mice, the researchers report in a new
scientific paper.

It's too soon to say if this could be mimicked in people to prevent plaque formation, but the researchers believe that further research is likely to
yield important insights that will benefit the battle against Alzheimer's.

The fact that amyloid beta production is normally tightly controlled
suggests that it may play an important role in brain cells, the
researchers say. As such, doctors may need to be careful in trying to
block or remove amyloid beta.

Additional research into the discovery could shed light on how to prevent
the over-production of amyloid beta as a strategy against Alzheimer's,
the researchers believe.

"If we can find strategies to prevent astrocytes from
over-producing cholesterol, we might make a real impact on the
development of Alzheimer's disease," Ferris said. "Once people
start having memory problems from Alzheimer's disease, countless
neurons have already died. We hope that targeting cholesterol
can prevent that death from ever occurring in the first place." ========================================================================== Story Source: Materials provided by
University_of_Virginia_Health_System. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Hao Wang, Joshua A. Kulas, Chao Wang, David M. Holtzman, Heather A.

Ferris, Scott B. Hansen. Regulation of beta-amyloid production
in neurons by astrocyte-derived cholesterol. Proceedings of the
National Academy of Sciences, 2021; 118 (33): e2102191118 DOI:
10.1073/pnas.2102191118 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210914100118.htm

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