Mitochondrial dysfunction may be one of the factors contributing to Alzheimer’s. Can researchers learn to fix it?
- Researchers have discovered that energy
production can be disrupted before the onset of Alzheimer’s disease.
- The mechanism underpinning this has not been
clear.
- A team of researchers have used nerve cell models
to decipher the part of the Krebs cycle that is disrupted in the
mitochondria of people with Alzheimer’s disease.
The brain uses up 20% of the body’s energy, and does so surprisingly efficiently.
Still, this makes it the most metabolically
demanding organ in the body, and cell signaling using this energy allows us to
carry out cognitive processes in the brain.
Disruption to energy metabolism and
therefore signaling between cells in the brain, can cause problems with
cognition, and research suggests that disruption to energy metabolism can occur before onset of
Alzheimer’s disease.
This is related to the dysfunction of mitochondria, the organelles
within cells that produce the energy that cells require.
Mitochondrial
dysfunction as neurological health disruptor
Dr. Clifford Segil, neurologist at Providence Saint John’s Health Center
in Santa Monica, CA, told Medical News Today in an email
that mitochondrial dysfunction is also involved in other conditions
He said that ”mitochondrial dysfunction is
well known to be involved in muscle disorders or myopathies.”
In addition, ”[a] condition called MELAS (mitochondrial
encephalomyopathy with lactic acidosis and stroke-like episodes) is something
we see infrequently but [is] tested [for] frequently.”
For these reasons, said Dr. Segil:
”It would make sense to
me that neurodegenerative diseases may be due to mitochondrial disease. Mitochondria
are the ‘powerhouses’ of cells and their dysfunction causes cells to not work
and in the brain, it is reasonable to think this would cause decreased
‘synapses’ or connection between cells.”
Energy
metabolism in Alzheimer’s disease
One recent study has shown that mitochondrial activity increased in neurons in
mouse models of Alzheimer’s disease, before disease onset.
This occurred alongside an increase in the
activity of genes involved in oxidative phosphorylation, a process that takes
place inside the mitochondria to produce energy.
Further experiments looking at the
connectors between neurons, called synapses, showed vesicles designed to
degrade proteins had accumulated in them, which affected signaling between
brain cells.
The ”hyperexcitability” of neurons
exhibited before Alzheimer’s disease onset has been a focus of existing
research.
A study published in Elife in 2019 showed
that models of neurons made using induced pluripotent stem cells taken from
people with Alzheimer’s disease showed a greater level of electronic signaling
due to increased excitatory and decreased inhibitory activity in the synapses.
This research was led by Prof. Stuart Lipton, professor and founding director at the Neurodegeneration New
Medicines Center, The Scripps Research Institute in La Jolla, CA.
It contributed toward the development of
the Alzheimer’s drug Namenda, which is used in patients with moderate to severe
Alzheimer’s disease to slow progression of the condition. It works by reducing
abnormal activity in the brain.
Can we
repair mitochondria in Alzheimer’s?
The team at Scripps Research have now used
nerve cell — also known as neurons — models, derived from skin biopsies from 40
people with and without a genetic mutation that causes Alzheimer’s disease, to
demonstrate a mechanism underpinning this mitochondrial dysfunction.
Moreover they wanted to demonstrate that
mitochondrial dysfunction can be fixed. This was a proof-of-concept study,
whose findings were published in Advanced Science.
Researchers analyzed glycolysis and
oxidative phosphorylation in these neuron models by looking at the proteins
that were expressed in the cells.
They found that the Krebs cycle, the
process that occurs in mitochondria to produce adenosine triphosphate (ATP), a molecule the body uses as energy, was disrupted in
the models.
They then grew the neuron models in
different media to inhibit different parts of the Krebs cycle. This allowed
them to identify the point at which the disruption occurred. They discovered
disruption to the formation of a molecule called succinate, a key point in the
cycle.
Further experiments showed that
introduction of a succinate analog that could pass through cell membranes
allowed energy production to be restored in three quarters of synapses where
signaling had been lost.
Lead author of this paper, Prof. Lipton,
told MNT that energy production is key for synapses to
function. He said: “We know that synapses, the connections between nerve cells,
are the best correlate to how demented you get with Alzheimer’s disease.
Furthermore, we know synapses require a lot of energy to maintain their
structure and function.
“When we found that the
new chemical reaction that we had discovered, termed protein S-nitrosylation
(or ‘SNOing’ a protein chemically) was decorating enzymes involved in energy
production and thus inhibited them, we reasoned that this decrement in energy
might be injuring the synapses. Moreover, this gave us the impetus to rescue
the energy, mostly formed in the mitochondria or energy powerhouse of the cell,
to rescue the synapses.”– Prof. Stuart Lipton
Opportunities
for future drug development
Although succinate and the molecule used in
this study cannot be administered as a drug, the team is now planning to
develop a drug target for this mechanism.
Prof. Lipton explained: “As you may
know, we are the group that developed and patented the FDA-approved drug
memantine (Namenda), which abates this excessive electrical activity, at least
in part. We are developing vastly improved drugs to do this that are working
their way through the FDA regulatory process. By way of disclosure, we have
formed a small biotech in the Boston area, named EuMentis Therapeutics, Inc.,
to perform this drug development.“
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