AI may help reveal new treatment pathways for Alzheimer’s disease.
- Research
has suggested that the gut microbiome is disrupted in people with
Alzheimer’s disease, and researchers from Ohio now propose this could be a
target for treatment.
- They
propose receptors that are present in the gut and brain could be the key
to targeting the gut-brain axis.
- Using
existing artificial intelligence (AI) tools researchers predicted which
metabolites, the by-products of bacteria in the gut, would bind with which
receptors by predicting their shape.
- They then used machine learning tools to predict which receptors and metabolites could have an influence on Alzheimer’s disease, and tested lab-created neurons to observe the effect of two metabolites on tau levels, a protein whose overaccumulation is linked to cognitive impairment.
- Machine learning has been used to predict how metabolites created in the gut bind with receptors found in the gut and brain.
A library of metabolites
and receptor binding pairs, recently created by researchers, could be used by
researchers to shed some light on the role of the microbiome in Alzheimer’s disease.
Researchers from the
Cleveland Clinic, OH recently evaluated the shapes of over 1 million potential
pairs of metabolites and receptors to see which ones might bind together.
By identifying which
metabolites bound with specific receptors, researchers were able to identify
the biological pathways these metabolites might affect, and also identify the
purpose of some receptors.
Lead author of the
research — which appears in Cell Reports — Feixiong
Cheng, PhD, director of the Cleveland Clinic Genome Center,
explained in a press release:
“Gut
metabolites are the key to many physiological processes in our bodies, and for
every key there is a lock for human health and disease. The problem is that we
have tens of thousands of receptors and thousands of metabolites in our system,
so manually figuring out which key goes into which lock has been slow and
costly. That’s why we decided to use AI.”
How does gut
health influence brain health?
The presence of certain
metabolites in the gut is partly indicative of the presence of certain bacteria
in the gut, as these metabolites are created via the breakdown of food in the
gut by the bacteria.
Alzheimer’s disease has previously been linked to changes in the gut microbiome in
humans, and it is likely that the gut affects brain health due to its role in
immune function.
Steve Gendron,
PhD, who specializes in immunology and endocrinology, and was not
involved in the recent study, made the following analogy in explaining the
potential mechanisms to Medical News Today:
“Imagine
the gut as a bustling market where all sorts of chemicals are being exchanged.
These chemicals can hop on the bloodstream express and make their way to Brain
Central Station. Scientists think this line of communication might influence
brain health because if the market (gut) starts selling the wrong stuff (like inflammatory
chemicals), it might contribute to the brain’s decline, seen in Alzheimer’s.
It’s a bit like if bad ingredients were used in a cake — you end up with a
baking disaster.”
While the role of the
immune system in Alzheimer’s disease is not well understood, research has linked inflammation to increased risk of
Alzheimer’s disease and chronic inflammation could play a role in the initiation
of the disease.
Cheng, the study’s lead
author, told MNT that “Alzheimer’s disease is a challenging
disease by lack of effective treatment.“
However, he added, the
“'[b]rain-gut axis’ has showed potential to treat brain disorders.“
“We
posit that [the] ‘brain-gut axis’ may be a good target for Alzheimer’s disease
drug development because we don’t have to deliver molecules/compounds to brain
via improving gut health.”– Feixiong Cheng, PhD
Using AI to
explore disease pathways in Alzheimer’s
If potentially harmful
binding of metabolites to receptors could be prevented, then potentially
Alzheimer’s disease risk could be reduced. To identify the binding pairs, the
researchers behind the current study first carried out a genetic analysis to
identify relationships between 408 receptors and Alzheimer’s disease.
Using the genetic code for these receptors
researchers used existing artificial intelligence (AI) resources to predict the
shape of the proteins that they code for. This gave a good idea of the shape of
the binding regions of the receptors.
Researchers were then
able to predict which metabolites would bind to these receptors and how. Most
of the metabolites discovered were lipid, or lipid-like metabolites.
New
treatment targets for Alzheimer’s?
They also looked at how
these receptors might respond to the microbiome of somebody with Alzheimer’s
disease. By investigating bacteria known to be abundant in the microbiome of
somebody with Alzheimer’s disease researchers identified two metabolites —
agmatine and phenethylamine, which are abundantly produced by Bacteroides
fragilis and Ruminococcus, respectively.
Researchers then decided
to observe the impact of these metabolites on the neurons of people with
Alzheimer’s disease by creating forebrain neurons using induced pluripotent
stem cells of people with Alzheimer’s disease.
They found that agmatine reduced levels of p-tau181,
p-tau205, and total tau. Further studies on phenethylamine showed that it
significantly reduced levels of p-tau181, p-tau205, and total tau in human
induced pluripotent forebrain neurons in a dose-dependent manner.
This is a promising
find, since overaccumulation of tau is associated with the development of
Alzheimer’s disease.
“In the current studies,
we only quantified tau phosphorylation because tau phosphorylation is a more
robust assay established by our lab and other scientists,“ Cheng said.
“We are doing more
preclinical [animal] studies to further test efficacy of gut metabolites (i.e.,
agmatine) and we may test it in future trials we get very successful in our
ongoing and future preclinical studies, including both safety in older
individuals and high efficacy,” he added.
The study authors point
out that 99% of clinical trials into pharmaceutical interventions for
Alzheimer’s disease have not been successful, and Cheng says their findings
could point to a new target:
“This
is exact[ly] our hypothesis: Improving gut health may influence the tau levels
in the brains and further prevent or even treat Alzheimer’s disease. However,
we need more research to be done in the future to investigate this hypothesis
further and we are working on it now using animal and human samples.”
Open access
resource for Alzheimer’s researchers
Other researchers are
welcome to use the findings from this study, in the hope it will help future
studies, Cheng told us.
“We are working on open
science approaches to help Alzheimer’s disease research community and help our
colleagues free access of all our ‘big data’ findings to guide their future
research to fight Alzheimer’s disease crisis,” said Cheng.
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