Summary: A common sleep medication, lemborexant, may
do more than promote rest—it appears to reduce harmful tau buildup and
protect the brain from neurodegeneration in mouse models of Alzheimer’s
disease. Researchers found that this orexin receptor antagonist not only
restored healthier sleep patterns but also preserved brain structure
and reduced inflammation.
Mice treated with lemborexant had up to
40% greater hippocampal volume than untreated controls or those given a
different sleep aid. Importantly, these neuroprotective effects were
seen only in male mice, which may reflect sex differences in tau
pathology severity.
Key Facts:
- Neuroprotection: Lemborexant reduced tau accumulation and brain cell death in male mice.
- Selective Mechanism: Only sleep aids blocking orexin receptors, like lemborexant, showed benefits.
- Structural Preservation: Treated mice had significantly larger hippocampal volumes, a region key to memory.
Source: WUSTL
A
common sleep aid restores healthier sleep patterns and protects mice
from the brain damage seen in neurodegenerative disorders, such as
Alzheimer’s disease, according to new research from Washington
University School of Medicine in St. Louis.
The drug,
lemborexant, prevents the harmful buildup of an abnormal form of a
protein called tau in the brain, reducing the inflammatory brain damage
tau is known to cause in Alzheimer’s.
The study suggests that
lemborexant and other drugs that work in the same way could help treat
or prevent the damage caused by tau in multiple neurodegenerative
diseases, including Alzheimer’s, progressive supranuclear palsy,
corticobasal syndrome and some frontotemporal dementias.
The study is published May 27 in Nature Neuroscience.
“We
have known for a long time that sleep loss is a risk factor for
Alzheimer’s disease,” said senior author David M. Holtzman, MD, the
Barbara Burton and Reuben M. Morriss III Distinguished Professor of
Neurology at WashU Medicine.
“In this new study, we have shown
that lemborexant improves sleep and reduces abnormal tau, which appears
to be a main driver of the neurological damage that we see in
Alzheimer’s and several related disorders.
“We are hopeful this
finding will lead to further studies of this sleep medication and the
development of new therapeutics that may be more effective than current
options either alone or in combination with other available treatments.
“The
antibodies to amyloid that we now use to treat patients with early,
mild Alzheimer’s dementia are helpful, but they don’t slow the disease
down as much as we would like,” he added.
“We need ways to reduce
the abnormal tau buildup and its accompanying inflammation, and this
type of sleep aid is worth looking at further. We are interested in
whether going after both amyloid and tau with a combination of therapies
could be more effective at slowing or stopping the progression of this
disease.”
Holtzman and his team were among the first to identify
the connection between poor sleep as a risk factor for Alzheimer’s
disease and the buildup of proteins such as amyloid and tau.
In
past work studying mice genetically prone to amyloid and tau buildup
characteristic of Alzheimer’s disease, they showed that sleep
deprivation makes this buildup worse. Improving sleep in these mice with
lemborexant appeared to be protective, the latest study showed, with
less buildup of tau protein tangles and less nerve cell death associated
with Alzheimer’s disease.
The protein tau accumulates in the
brain in multiple neurological disorders, including Alzheimer’s, and
causes inflammation and the death of brain cells. Holtzman and his team,
co-led by first author Samira Parhizkar, PhD, an instructor in
neurology, tested lemborexant in part because it has effects in parts of
the brain known to be affected by abnormal tau accumulation.
It also does not impair motor coordination, which is a concern for people with dementia taking hypnotic sleep aids.
Lemborexant
is one of three sleep drugs approved by the Food and Drug
Administration that inhibit the effect of orexins, small proteins that
regulate sleep, by acting as orexin receptor antagonists. Lemborexant
blocks both orexin receptors (type 1 and type 2).
Receptors are
proteins on the cell surface that bind to other molecules and regulate
cell activity. These receptors are known to play important roles in
sleep-wake cycles and appetite, among other physiological processes.
The
pharmaceutical company Eisai provided lemborexant for these studies as
part of a research collaboration with WashU Medicine focused on
developing innovative treatments for Alzheimer’s disease, Parkinson’s
disease and other neurodegenerative diseases.
In mice genetically
prone to harmful tau buildup, lemborexant reduced brain damage compared
with control mice. For example, those receiving lemborexant showed 30%
to 40% larger volume in the hippocampus — a part of the brain important
for forming memories — compared with control mice and those receiving a
different sleep drug, zolpidem, which belongs to a different class of
drugs.
Zolpidem increased sleep but had none of the protective
effects against tau accumulation in the brain that were seen with
lemborexant, suggesting that the type of sleep aid — orexin receptor
antagonist — is key in producing the neuroprotective effects.
The researchers also found that the beneficial effects were only seen in male mice, which they are still working to understand.
Normal
tau is important in maintaining the structure and function of neurons.
When healthy, it carries a small number of chemical tags called
phosphate groups. But when tau picks up too many of these chemical tags,
it can clump together, leading to inflammation and nerve cell death.
The
authors found that by blocking orexin receptors, lemborexant prevents
excess tags from being added to tau, helping tau maintain its healthy
roles in the brain.
Holtzman said his team is continuing to
explore the reasons lemborexant treatment’s neuroprotective effects were
seen only in male mice.
He speculated that the sex discrepancy
could be due to the observation that female mice with the same genetic
predisposition to tau accumulation developed less-severe
neurodegeneration compared with male mice. With less damage to begin
with, potential beneficial effects of the drug could have been smaller
and more difficult to detect.
Funding: This work
was supported by the National Institutes of Health (NIH), grant numbers
P01NS074969, RF1NS090934 and RF1AG061776; the JPB Foundation; the
Alzheimer’s Association, grant number AARF-21-850865; the Rainwater
Foundation, and a COBRAS Feldman Fellowship.
Holtzman is an
inventor on a patent licensed by Washington University to C2N
Diagnostics on the therapeutic use of anti-tau antibodies. Holtzman
cofounded and is on the scientific advisory board of C2N Diagnostics.
About this neuropharmacology and Alzheimer’s disease research news
Author: Jessica Church
Source: WUSTL
Contact: Jessica Church – WUSTL
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Lemborexant ameliorates tau-mediated sleep loss and neurodegeneration in males in a mouse model of tauopathy” by David M. Holtzman et al. Nature Neuroscience
