Breakthrough discovery restores neural connections in Alzheimer’s patients
Scientists uncover mitochondrial dysfunction as a key factor in Alzheimer’s, offering hope through groundbreaking treatments targeting energy deficits
Researchers reveal how restoring mitochondrial energy production could halt Alzheimer’s progression. (CREDIT: CC BY-SA 4.0)
The human brain is a complex powerhouse, responsible for orchestrating thoughts, emotions, and memories. Its nerve cells require an immense amount of energy to function.
This energy is critical for maintaining the connections between neurons that enable effective communication. However, in Alzheimer's disease, this essential energy production falters, leading to the deterioration of neural connections and the progressive loss of memory.
A groundbreaking study published in Advanced Science by researchers at Scripps Research sheds light on this energy crisis. The team delved into the mitochondrial dysfunction underlying Alzheimer’s neurodegeneration, identifying the mechanisms at play and exploring potential therapeutic solutions.
By targeting a malfunction in the mitochondria, these cellular power plants, the researchers achieved remarkable results: restoring many neuron-to-neuron connections in nerve cell models derived from human Alzheimer's patient stem cells.
Understanding the Mitochondrial Crisis
Mitochondrial deficits and bioenergetic compromise have long been implicated in Alzheimer’s disease and other neurodegenerative disorders.
Research has linked synaptic loss in Alzheimer’s brains to mitochondrial dysfunction, which represents a key factor in cognitive decline. The culprit behind this energy loss lies within the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle—a vital process in cellular energy production.
Central to the dysfunction is the aberrant modification of mitochondrial enzymes by S-nitrosylation, a chemical reaction where nitrogen and oxygen atoms bind to sulfur atoms on proteins. This alteration, termed a “SNO-tag,” disrupts the function of enzymes essential for energy production, particularly α-ketoglutarate dehydrogenase (αKGDH).
A study of Alzheimer’s brains revealed an overabundance of these modified enzymes, forming what researchers dubbed a "SNO-Storm."
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Using advanced techniques, such as 13C dynamic labeling and the Seahorse platform to measure oxygen consumption rates (OCR), the researchers pinpointed significant deficits in the TCA cycle.
These findings were confirmed in both human postmortem Alzheimer’s brains and in neurons derived from Alzheimer’s patient stem cells. The neurons exhibited reduced mitochondrial respiration and impaired energy production, correlating with the extensive S-nitrosylation of critical enzymes.
The Role of Succinate and the Krebs Cycle
One key discovery was a bottleneck in the Krebs cycle, specifically in the production of succinate, a molecule crucial for generating ATP—the primary energy source of cells. This bottleneck prevents the mitochondria from producing adequate energy, compromising the survival of neurons and their intricate network of synapses.
The research team hypothesized that replenishing succinate could restore energy production. However, succinate faces challenges in crossing nerve cell membranes. To overcome this, the scientists used a succinate analog capable of penetrating cells effectively. This approach successfully repaired up to 75% of the lost synapses in their models, providing a potential pathway to rescue neuronal connectivity.
“Succinate is not a compound that people can now take as a treatment, but it’s proof-of-principle that you can re-energize the Krebs cycle,” explained Dr. Stuart Lipton, senior author of the study. He emphasized the need for further research to develop a safe and effective energy-restoring drug for humans.
The implications of this research extend far beyond the laboratory. Dr. Lipton, a seasoned clinical neurologist and the Step Family Foundation Endowed Professor at Scripps Research, has a track record of developing treatments for Alzheimer’s, including Namenda®. His team’s findings highlight mitochondrial metabolism as a promising therapeutic target for Alzheimer’s and related neurodegenerative diseases.
The study also underscores the importance of understanding the broader mechanisms underlying energy deficits in Alzheimer’s. Posttranslational modifications, such as S-nitrosylation, represent critical control points in bioenergetics. While this research focused on αKGDH, other enzymes within the TCA cycle may also be affected, necessitating further investigation.
Beyond their immediate findings, the researchers’ use of human-induced pluripotent stem cell (hiPSC) models provides a valuable tool for studying Alzheimer’s at the cellular level. By generating neurons from stem cells derived from Alzheimer’s patients, the team was able to replicate disease-relevant metabolic changes and identify therapeutic targets with high precision.
The Road Ahead
While the findings offer hope, the journey toward an effective treatment remains challenging. Developing drugs capable of safely restoring mitochondrial function will require rigorous testing and clinical trials. Additionally, the complexity of Alzheimer’s disease means that targeting energy deficits may need to be combined with other therapeutic strategies to address the multifaceted nature of the condition.
Dr. Lipton’s team is committed to advancing this line of research. By exploring innovative approaches to re-energize the Krebs cycle, they aim to halt disease progression and improve cognitive outcomes for patients. “We thought that if we could repair metabolic activity in the mitochondria, maybe we could salvage the energy production,” Dr. Lipton remarked. This vision reflects the determination of researchers worldwide to confront Alzheimer’s with scientific ingenuity and compassion.
In a world where Alzheimer’s disease robs millions of their memories and independence, breakthroughs like this bring a glimmer of hope.
By addressing the fundamental energy crisis in the brain, scientists are paving the way for treatments that could preserve not only neurons but also the connections that define our humanity.
Who has Alzheimer’s Disease?
- In 2020, as many as 5.8 million Americans were living with Alzheimer’s disease.
- Younger people may get Alzheimer’s disease, but it is less common.
- The number of people living with the disease doubles every 5 years beyond age 65.
- This number is projected to nearly triple to 14 million people by 2060.
- Symptoms of the disease can first appear after age 60, and the risk increases with age.
What is known about Alzheimer’s Disease?
Scientists do not yet fully understand what causes Alzheimer’s disease. There likely is not a single cause but rather several factors that can affect each person differently.
- Age is the best known risk factor for Alzheimer’s disease.
- Family history—researchers believe that genetics may play a role in developing Alzheimer’s disease. However, genes do not equal destiny. A healthy lifestyle may help reduce your risk of developing Alzheimer’s disease. Two large, long term studies indicate that adequate physical activity, a nutritious diet, limited alcohol consumption, and not smoking may help people.
- Changes in the brain can begin years before the first symptoms appear.
- Researchers are studying whether education, diet, and environment play a role in developing Alzheimer’s disease.
- There is growing scientific evidence that healthy behaviors, which have been shown to prevent cancer, diabetes, and heart disease, may also reduce risk for subjective cognitive decline.
What is the burden of Alzheimer’s disease in the United States?
- Alzheimer’s disease is one of the top 10 leading causes of death in the United States.
- The 6th leading cause of death among US adults.
- The 5th leading cause of death among adults aged 65 years or older.
- In 2020, an estimated 5.8 million Americans aged 65 years or older had Alzheimer’s disease. This number is projected to nearly triple to 14 million people by 2060.
In 2010, the costs of treating Alzheimer’s disease were projected to fall between $159 and $215 billion. By 2040, these costs are projected to jump to between $379 and more than $500 billion annually.
Death rates for Alzheimer’s disease are increasing, unlike heart disease and cancer death rates that are on the decline.
Dementia, including Alzheimer’s disease, has been shown to be under-reported in death certificates and therefore the proportion of older people who die from Alzheimer’s may be considerably higher.
Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.
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