• 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.

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.”

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.

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

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.“

“We are looking at inflammatory pathways and other routes to nerve cells damage in [Alzheimer’s disease] as well using these human model systems. Importantly, these are real human neurons created from patient stem cells, so they faithfully re-create the disease in several aspects,” he noted.

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