Research shows that Alzheimer’s disease affects many organs beyond the nervous system.
- Alzheimer’s is characterized
by a buildup of proteins in the brain, which disrupts their function.
- A new study in fruit flies
shows that these proteins may also significantly impact the functioning of
other organs.
- The researchers also
identified mechanisms that might explain how proteins in the brain can
have such wide-reaching effects.
A new study in fruit
flies concludes that proteins associated with Alzheimer’s disease not only
influence brain health, but also have effects further afield.
Specifically, the researchers show that certain
Alzheimer’s-associated proteins can increase the rate of biological aging and
influence fat metabolism and reproduction.
They also created an
Alzheimer’s Disease Fly Cell Atlas (AD-FCA) based on their analysis of 219 cell
types in flies that express Alzheimer’s-associated proteins in their brains.
The results recently
appeared in the journal NeuronTrusted Source.
How dementia affects the body
Alzheimer’s and other
dementias are considered diseases of the mind, and for good reason. The primary
symptoms are cognitive changes that grow progressively more severe as time goes
on.
For this reason, much of
the research into dementia focuses on the brain and nervous system.
However, more recently, scientists have begun exploring Alzheimer’s influence
on other aspects of the body.
The authors of the new study explain how new
evidence hints that the effects of Alzheimer’s extend beyond the nervous system
to other parts of the body. “For example,” they write, Alzheimer’s “has been
associated with disruptions in the gut microbiota, cardiovascular function, and
hormone homeostasis.”
They also explain
how inflammation
and reduced immune healthTrusted Source can contribute to Alzheimer’s progression.
Clearly, Alzheimer’s is not confined to the brain.
Alzheimer’s protein and the fly model
Alzheimer’s disease is
characterized by a buildup of faulty proteins in the brain, including
amyloid-beta 42 and tau.
As they accumulate, they
form so-called amyloid plaques and neurofibrillary tangles, respectively. These
proteins interfere with how neurons work and, eventually, kill them.
In their recent study,
the researchers used fruit flies. Although fruit flies, as you may have
noticed, are quite different from humans, they have already provided many
insights into human health.
As the researchers
write, “Many molecular pathways are conserved from flies to mammals.”
Medical News Today contacted Gurneet Sawhney, MD, chief neurosurgeon and founder at Neurolife Brain and Spine Clinic,
who was not involved in the study. We asked about the usefulness of fly models
in neuroscience.
“Fruit fly models are surprisingly valuable in
dementia research. While they may seem simplistic,” he explained, “they allow
us to study the effects of tau and amyloid at a genetic and cellular level,
with faster results and lower complexity than mammalian models.”
“They’ve helped us
uncover fundamental mechanisms of neurodegeneration that often translate into
mammalian systems later,” he said.
In the current
experiment, the scientists used flies with either amyloid or tau buildup and
compared them with control flies without protein buildup.
The researchers employed
a technique called whole-organism single-nucleus RNA sequencingTrusted Source. In a nutshell, this involves analyzing genetic information from cell
nuclei to discover which genes are turned “on” in specific cell types.
The widespread impact of tau and
amyloid
The authors investigated
the impact of tau and amyloid on a range of cell types throughout the flies’
bodies.
Amyloid’s
effects on the nervous system
First, they examined the
cells of the nervous system, including brain cells, nerve cells in their body,
and glial cells (support cells for neurons).
They found that amyloid
resulted in the loss of many types of these cells compared with tau and control
flies.
In particular, cells involved with the senses, such
as vision, hearing, and smell, were impacted most severely.
Interestingly, loss of
smell is an early sign of Alzheimer’s in humans.
When investigating the
mechanism responsible for neuronal cell death, the researchers identified a
cluster of neuronal cells that expressed lactate dehydrogenase (LDH). We asked
Sawhney why this matters:
“LDH plays a role in
cellular energy metabolism,” he explained, “and its dysregulation can indicate
tissue stress or damage. In the context of dementia, abnormal LDH activity
might reflect broader metabolic dysfunction.”
Importantly, the
scientists also identified increased levels of LDH in the brain tissue from
humans with Alzheimer’s but not those without the condition. According to
Sawhney, this increased LDH may “link neurodegeneration with systemic effects,
as this study hints.”
The scientists also
showed that cells with elevated LDH had changes in genes that control
mitochondrial functions. This is important because mitochondrial dysfunction is
linked to oxidative stress, which is an early feature of Alzheimer’s in humans.
Tau’s effects on
the body
Next, the scientists
moved their attention to the effects of Alzheimer’s proteins on cells other
than those of the nervous system. This time, it was tau that produced the most
significant changes.
The cell types that were most affected were those
involved in fat metabolism, digestion, and reproduction. According to the
authors, “The fly fat body is a central storage depot of nutrients and energy
reserves.” It carries out a similar role to the liver, immune system, and fat
tissue in mammals.
They found that fat
droplets in tau flies are large early on, but become smaller and more
fragmented as the disease progresses. The researchers then looked at fat cells
in a mouse model of Alzheimer’s — the equivalent of the fly’s fat droplets.
Again, they found oversized fat cells initially, which grew smaller as the
disease progressed.
Interestingly, other
scientists have shown that the activity of certain types of fat may influence
Alzheimer’s development in
humans, too.
Aside from changes in
fat metabolism, the researchers noted changes in the behaviour of cells in the
gut. In line with this, studies in mice have also shown that tau induces gut degenerationTrusted Source.
Finally, neuronal tau
was associated with a reduced ability to reproduce in male flies. In
concordance with this, studies show that a decline in sex
hormones is associated with an
increased risk of Alzheimer’s in humans.
Tau’s effects on
cellular aging
According to the
authors, changes in fat metabolism, digestion, and reproduction are associated
with aging. So, the authors hypothesize that tau’s presence in neurons may
increase the speed of aging throughout the rest of the body.
By measuring gene expression and molecular markers
associated with fly aging, the scientists found that tau flies, but not amyloid
or control flies, aged more quickly.
Overall, they conclude
that “Tau expression has a broad impact on peripheral tissues and induces an
accelerated aging phenotype.”
How does tau in the brain impact
the body?
To understand how tau in
neurons has such wide-ranging effects on the body, the scientists used cell-cell
communication analysis, which can
identify changes in how the brain communicates with the body.
Compared with amyloid
and control flies, tau flies demonstrated thousands of differences in these
communication pathways. The cell types showing the greatest differences, once
again, were involved with fat metabolism, digestion, and reproduction.
These results suggest that tau in the brain can
influence cells in the rest of the body by interfering with brain-body
communication.
Investigating further,
they found that in neurons containing tau, there were changes in the gene
expression that affected how synapses — the junction between nerve cells — are
organized.
There were also increased
levels of synaptic boutons in the gut of tau flies. The synaptic boutons are
swellings on nerves at the synapse that contain neurotransmitters, which pass information from one neuron to another.
In other words, tau in
brain cells can influence not only how neurons work and develop within the
brain but also how effectively they communicate with more distant tissues.
Alzheimer’s impact extends beyond
the brain
Overall, the scientists
conclude that while amyloid and tau are both toxic, their effects are distinct:
Amyloid predominantly affects neurons, and tau has a more widespread impact on
the body.
They also found that LDH
is elevated in amyloid flies, as well as in mice and humans with Alzheimer’s.
They believe this should be an area for future research, as LDH could perhaps
be used as an early biomarker for Alzheimer’s.
Research on flies is an
important first step in scientific research; it provides direction for future
studies on other animals and, eventually, humans.
While we need to interpret the results with caution,
taken together, they provide new insights into the widespread effects of
Alzheimer’s-associated proteins.
“The focus on the
peripheral effects of tau and amyloid stands out in this study,” Sawhney
told MNT.
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