In Alzheimer's disease and related dementias, cognitive decline is
driven by the overaccumulation of a normal brain protein known as tau.
Wherever tau builds up, nearby brain tissue starts to degenerate and
die.
Now, researchers at Washington University School of Medicine in St.
Louis have found — in mice — that Alzheimer's-like tau deposits in the
brain lead to the accumulation of a form of cholesterol known as
cholesteryl esters, and that lowering cholesteryl ester levels helps
prevent brain damage and behavioral changes.
This has important therapeutic implications. The compound we used in
this study has side effects that make it unsuitable for use in people.
But if you could develop a therapy that reduces cholesteryl esters
inside brain cells without unacceptable side effects, it would be a
promising candidate to test in neurodegenerative diseases."
David M. Holtzman, MD, Senior Author, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology
The findings are published Nov. 22 in the journal Neuron.
The link between cholesterol and dementia is not as far-fetched as it
might seem. The biggest genetic risk factor for Alzheimer's is APOE,
a gene involved in activating the brain's immune cells. When such cells
are activated in the wrong way or at the wrong time, they can damage
brain tissue. But APOE also has another important job in the body: It
carries cholesterol and other lipids around in the blood. In this
capacity, it plays a role in atherosclerosis.
To investigate the connections between APOE, lipids and brain damage,
Holtzman and first author Alexandra Litvinchuk, PhD, a postdoctoral
researcher, studied mice with a high-risk tau gene that predisposes them
to accumulate tau in their brains. Such mice start developing signs of
neurodegeneration around 6 months of age. By 9½ months, their brains are
severely damaged, and they no longer are able to complete ordinary
tasks of mouse life such as properly building a nest. The mice also
carried a second genetic modification: Their own APOE genes had been removed and either replaced with a variant of the human APOE gene — APOE3, which confers an average risk of Alzheimer's; or APOE4, which doubles or triples the risk of Alzheimer's — or not replaced at all.
Investigation revealed that APOE4 is linked to distorted lipid metabolism in the brain. In 9½-month-old tau mice carrying APOE4,
the same brain areas that became atrophied and damaged also amassed
excess lipids, and in a strange pattern. Levels of more than 180 kinds
of lipids were altered. Among the most striking differences was that
immune cells known as microglia in those areas were filled to the brim
with cholesteryl esters. APOE3 did not have the same effect.
The measurement of the brain lipids was done in collaboration with
scientists at the company Denali Therapeutics led by Gilbert Di Paolo,
PhD.
"Microglia
filled up with lipids become hyperinflammatory and start secreting
things that are not good for the brain," Holtzman said.
Therefore, clearing out lipids potentially could reduce brain
inflammation and neurodegeneration, he said. To find out, Litvinchuk and
Holtzman used an LXR agonist, a member of an experimental class of
drugs that lowers lipid levels in cells. The researchers fed the drug,
called GW3965, to tau mice carrying APOE4, starting at 6 months
of age. The mice were assessed at 9½ months, by which point their
brains normally would have sustained considerable damage. Mice that had
received the drug retained significantly more brain volume than those
that had received a placebo. They also had lower levels of tau, fewer
inflammatory cells and less inflammation, less loss of synapses in their
brains, and were better at building nests.
Further investigation revealed that the LXR agonist works by upregulating a gene called Abca1
that helps move cholesterol and other lipids out of cells. Using
genetic methods to increase Abca1 levels had the same effect as drug
treatment: less lipid accumulation, lower levels of tau, less
inflammation and reduced neurodegeneration.
"What's exciting is that we see all these effects in an animal model
that shares a lot of features with human neurodegenerative diseases,"
Holtzman said. "It shows that this kind of approach could have a lot of
promise."
One major obstacle stands in the way of translating this approach to
people, Holtzman added. LXR agonists also affect lipid metabolism in the
liver, and so they tend to cause fatty liver disease.
Chemists are hard at work trying to design LXR agonists without that
side effect. If they succeed, the resulting drugs may have benefits for
heart disease as well as brain disease.
"There's a lot of similarity between the mechanism that's driving
immune cells to damage the brain in Alzheimer's disease and the one
that's driving the same kinds of immune cells to cause vascular damage
in atherosclerosis," Holtzman said. "In both cases, lipids accumulate in
immune cells, causing them to become hyperinflammatory and damage
nearby tissues. Getting rid of that lipid accumulation may have double
benefits for human health."
Source:
Journal reference:
Litvinchuk, A., et al. (2023) Amelioration of Tau and ApoE4-linked glial lipid accumulation and neurodegeneration with an LXR agonist. Neuron. doi.org/10.1016/j.neuron.2023.10.023.
