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New study reveals the root cause of Alzheimer's disease brain malfunctions

[Jan. 30, 2024: JD Shavit, The Brighter Side of News]

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.

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.


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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."


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.

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)

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.


Dr. Silvia Maioli, an Associate Professor at the Department of Neurobiology, Care Sciences, and Society at Karolinska Institutet, led the study and expressed optimism about the findings. She stated, "Cholesterol turnover and sex hormones are modifiable factors. Our results suggest that they may serve as potential treatment targets for several neurodegenerative diseases in the future."

The study, primarily conducted on mice, centered on the activation of the brain protein CYP46A1, which appears to play a crucial role in protecting women from developing neurodegenerative conditions, including Alzheimer's disease. This protein is responsible for converting excess cholesterol in the brain into a specialized cholesterol product known as 24S-hydroxycholesterol (24SOH).

In their experiments, researchers increased the levels of CYP46A1 in both male and female mice. This augmentation resulted in higher production of 24SOH. Strikingly, in female mice, this led to observable improvements such as healthier neurons, enhanced memory capacities, and increased estrogen activity.

These positive effects were particularly significant in situations simulating menopause and aging. Intriguingly, male mice did not exhibit similar benefits.


One key revelation from the study was that higher levels of 24SOH in the cerebrospinal fluid of Alzheimer's patients correlated with reduced levels of Alzheimer's markers, specifically tau protein—but this correlation was exclusive to women.

Alzheimer's disease disproportionately affects women, with approximately two-thirds of individuals diagnosed being female. Early menopause, which involves the decline of estrogen production, is recognized as a specific risk factor for cognitive decline.

Estrogen, produced not only in the ovaries but also in the brain, plays a crucial role in maintaining the health and functionality of neurons. The activation of CYP46A1 was found to increase estrogen activity in the brains of menopausal and elderly female mice, offering a promising avenue for targeted therapy.


Dr. Maioli explained, "Previous research has shown that CYP46A1 can be activated pharmacologically with low doses of the anti-HIV drug Efavirenz. We believe that targeting cholesterol metabolism by CYP46A1 activators such as Efavirenz may offer a new approach to promote estrogen-mediated neuroprotection in women at risk of Alzheimer's disease."

Golgi staining of mouse brain tissue. (CREDIT: Silvia Maioli laboratory)

The study was meticulously conducted under the guidance of Dr. Silvia Maioli and doctoral student Maria Latorre Leal. It included experiments with genetically modified mice, encompassing behavioral studies and molecular analyses. In their pursuit of understanding the underlying biological mechanisms, researchers also explored cultured hippocampal neurons.


To validate the clinical significance of their findings, biomarkers were measured in cerebrospinal fluid from a cohort of patients at the memory clinic of Karolinska University Hospital. Notably, the analyses were gender-specific and carried out in collaboration with experts from various institutions, including Miia Kivipelto's and Bengt Winblad's group, Henrik Zetterberg, and Kaj Blennow in Gothenburg, as well as researchers at Swansea University.

Maria Latorre Leal and Silvia Maioli, Division of Neurogeriatrics, NVS. (CREDIT: Andreas Andersson)

The research received crucial support from funding sources such as the Margaretha af Ugglas Foundation, the private initiative "Innovative ways to fight Alzheimer's disease - Leif Lundblad Family, the NIH R01 grant, and the King Gustaf V:s and Queen Victoria's Foundation.


This study represents a significant stride toward understanding and potentially combating neurodegenerative diseases, particularly Alzheimer's, that disproportionately affect women. The activation of the CYP46A1 brain protein offers a glimmer of hope in the quest to protect the cognitive health of women at risk of Alzheimer's disease. The implications of this research are profound and may pave the way for innovative therapeutic approaches in the future.

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.

For more science news stories check out our New Discoveries section at The Brighter Side of News.


Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.


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