Groundbreaking study reveals the root cause of brain malfunctions due to Alzheimer's disease
The study has delved deep into the energetic reactions within brain cells that malfunction and trigger neurodegeneration in Alzheimer's patients. (CREDIT: Creative Commons)
In neuroscience, the brain remains an enigmatic powerhouse, orchestrating complex cognitive processes, preserving memories, and maintaining the body's vital functions. Yet, beneath its intricate machinery, lies an astonishing fact: nerve cells in the brain demand an enormous amount of energy to survive and thrive.
This energy is essential for maintaining connections between nerve cells, enabling them to communicate effectively. Unfortunately, in the case of Alzheimer's disease, this crucial energy production becomes compromised, leading to the deterioration of these vital connections and the subsequent fading of cherished memories.
A groundbreaking study conducted by a team of researchers at Scripps Research, published in the journal Advanced Science, has delved deep into the energetic reactions within brain cells that malfunction and trigger neurodegeneration in Alzheimer's patients.
Alzheimer's nerve cells manifest a decrease in the connections between nerve cells, called synapses, shown here within the blue circles. Half the synapse is marked with a red fluorescent stain and the other half with a yellow stain. (CREDIT: Scripps Research)
By harnessing the power of a small molecule to address this malfunction within the mitochondria—the energy production centers of cells—the researchers have successfully restored numerous neuron-to-neuron connections in nerve cell models derived from human Alzheimer's patient stem cells.
This remarkable breakthrough highlights the potential of improving mitochondrial metabolism as a promising therapeutic target for Alzheimer's and related disorders.
Dr. Stuart Lipton, senior author of the study, a renowned clinical neurologist, and the Step Family Foundation Endowed Professor at Scripps Research, expressed the team's motivation, stating, "We thought that if we could repair metabolic activity in the mitochondria, maybe we could salvage the energy production."
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Utilizing human neurons derived from Alzheimer's patients, the researchers aimed to protect and restore energy levels, ultimately rescuing a significant number of neuronal connections.
The heart of this groundbreaking research lies in the identification of a critical problem: a blockage in the enzymes responsible for energy production, caused by an abnormal tag composed of nitrogen (N) and oxygen (O) atoms attached to a sulfur (S) atom. This dysfunctional "SNO" enzyme arises from a reaction known as S-nitrosylation, and the team discovered that this reaction ran rampant in the neurons of Alzheimer's-afflicted brains, aptly naming it a "SNO-Storm."
To unravel the mystery of this "SNO-tag" on energy enzymes, Dr. Lipton and his colleagues embarked on a comprehensive investigation. They compared human brains from Alzheimer's patients, obtained post-mortem, with those from individuals without any brain disease.
Schema showing effects of S-nitrosylation (SNO) of TCA cycle enzymes in isogenic WT/Control and AD mutanthiN. AD-hiN displays basal partial inhibition of the TCA cycle at the Aco/IDH steps. (CREDIT: Advanced Science)
The next step involved generating nerve cells from stem cells derived from skin biopsies of both Alzheimer's patients and those without a genetic mutation predisposing them to the disease. Armed with metabolic labels and an oxygen-measuring apparatus, the researchers meticulously measured cellular energy production, pinpointing unique deficits in Alzheimer's nerve cells compared to their healthy counterparts.
One of the key findings was the disruption of the Krebs cycle within mitochondria, a cellular process that generates the body's primary molecular energy source, ATP. The team identified a bottleneck in the Krebs cycle, specifically in the production of succinate, a molecule critical for ATP production. This bottleneck hampered the mitochondria's ability to supply the energy necessary for the survival of neurons and their intricate network of connections.
The researchers theorized that replenishing the missing succinate molecules might rejuvenate energy production, essentially kickstarting the stalled mitochondrial Krebs cycle. Succinate, however, faces challenges in crossing nerve cell membranes.
To overcome this hurdle, the scientists employed an analog that could efficiently traverse these barriers. The strategy proved successful, leading to the repair of up to three-quarters of the lost synapses and halting further decline.
Dr. Lipton emphasizes, "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." He acknowledges the need for more research to develop a safer and more effective energy-preserving drug for humans.
His history of developing FDA-approved drugs for Alzheimer's, such as Namenda®, underscores his commitment to advancing treatments for the disease. His laboratory will continue to explore the mitochondrial Krebs cycle as a promising therapeutic avenue, with the ultimate goal of restoring neuronal connectivity in Alzheimer's patients, thereby arresting disease progression and enhancing cognitive function.
In a world plagued by Alzheimer's, where memories are stolen and connections severed, this recent breakthrough offers a glimmer of hope for millions.
While the path to a viable treatment remains long and arduous, the dedication of researchers like Dr. Stuart Lipton fuels optimism that one day, Alzheimer's may no longer be an insurmountable foe, and cherished memories may endure.
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.
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