Brain cholesterol regulates Alzheimer's plaques, study reveals
Advanced imaging technique shows how cholesterol regulates production of Alzheimer's-associated amyloid beta protein in a type of brain cell

Date:
August 13, 2021
Source:
Scripps Research Institute
Summary:
The production of the Alzheimer's-associated, toxic protein amyloid
beta in the brain is tightly regulated by cholesterol in the cell
membrane, advanced imaging reveals.



FULL STORY ==========================================================================
A team co-led by scientists at Scripps Research has used advanced imaging methods to reveal how the production of the Alzheimer's-associated protein amyloid beta (Ab) in the brain is tightly regulated by cholesterol.


========================================================================== Appearing on line Thursday ahead of print in the Aug. 17 issue of the Proceedings of the National Academy of Sciences (PNAS), the scientists'
work advances understanding of how Alzheimer's disease develops and
underscores the long-underappreciated role of brain cholesterol. The
findings also help explain why genetic studies link Alzheimer's risk to
a cholesterol-transporting protein called apolipoprotein E (apoE).

"We showed that cholesterol is acting essentially as a signal in
neurons that determines how much Ab gets made -- and thus it should
be unsurprising that apoE, which carries the cholesterol to neurons,
influences Alzheimer's risk," says study co-senior author Scott Hansen,
PhD, an associate professor in the Department of Molecular Medicine at
Scripps Research, Florida.

The other co-senior author of the study was Heather Ferris, MD, PhD,
assistant professor in the Department of Medicine at the University of
Virginia School of Medicine. The study's first author, Hao Wang, is a
graduate student in the Hansen lab.

Understanding Ab A type of Ab in the Alzheimer's brain can form large, insoluble aggregates that gather in extensive clumps or "plaques" --
one of the most prominent features of the disease at autopsy. Genetic
evidence correlates the production of a subtype of Ab with Alzheimer's,
yet Ab's role in both the healthy brain and in disease remain a subject
of debate, after many clinical trials of Ab-clearing therapeutics have struggled to show a benefit.



==========================================================================
In the new study, Hansen and his colleagues take a close look
cholesterol's connection to Ab production. Cholesterol's role has been suggested by various prior studies but never confirmed directly, due to technological limitations.

The scientists used an advanced microscopy technique called
super-resolution imaging to "see," in cells and in the brains of live
mice and tracked how cholesterol regulates Ab production.

They focused on cholesterol produced in the brain by essential helper
cells called astrocytes, and saw it was carried by apoE proteins to the
outer membranes of neurons. There, it appeared to help maintain clusters
of cholesterol and related molecules colloquially referred to as "lipid
rafts." Lipid rafts are not yet well understood, in part because they
are too tiny to image with ordinary light microscopes. With improved technology, they are increasingly appreciated as hubs where signaling
molecules come together to carry out key cellular functions.

The protein from which Ab is produced, APP, also sits in neuronal
membranes.

The researchers showed that apoE and its cholesterol cargo bring APP
into contact with nearby lipid rafts. There, in the rafts, enzymes that
cleave APP to form Ab are found. They found that blocking the flow of cholesterol would take APP out of contact with lipid rafts, thereby
effectively preventing Ab production.

Cholesterol and brain health The scientists then did a series of
experiments in aged "3xTg-AD" mice, which are genetically engineered
to overproduce Ab, to develop Ab plaques, and broadly to model
Alzheimer's. They found that when they shut off astrocyte cholesterol production in the mice, Ab production plummeted to near-normal, and Ab
plaques virtually disappeared. Another classic Alzheimer's sign usually
seen in these mice is the accumulation of tangled aggregates of a neuronal protein called tau -- and those disappeared too.



==========================================================================
By confirming and clarifying the role of astrocyte-produced cholesterol
in Ab production, the study suggests that targeting this process is
worthy of exploration for potential to prevent Alzheimer's progression.

Hansen notes, however, that cholesterol is needed by the brain for
many other processes, including the maintenance of normal alertness
and cognition. His laboratory discovered in a 2020 study that severely interrupting the effect of cholesterol in neurons by general anesthetics
can induce unconsciousness via a shared mechanism.

"You couldn't just eliminate cholesterol in neurons, cholesterol is needed
to set a proper threshold for both Ab production and normal cognition,"
Hansen says.

The findings offer new evidence of the underlying factors advancing
development of Alzheimer's. A common variant of the apoE gene, known as
the E4 variant, is the largest risk factor for late-onset Alzheimer's,
and Hansen and colleagues found evidence in the study that this variant, compared to the more common, lower-risk E3 variant, somehow boosts APP's association with lipid rafts, which thus boosts Ab production.

Hansen and his laboratory are currently studying how apoE's transport
of cholesterol and maintenance of lipid rafts in the brain impacts
not only Ab production but also brain inflammation -- another feature
of Alzheimer's that contributes to destruction in the brain but has
murky causes.

"There is the suggestion here of a central mechanism, involving
cholesterol, that could help explain why both Ab plaques and inflammation
are so prominent in the Alzheimer's brain," Hansen says.

========================================================================== Story Source: Materials provided by Scripps_Research_Institute. 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/2021/08/210813151957.htm

--- up 14 weeks, 22 hours, 45 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)