It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
Tuesday, October 17, 2023
Fungal infection in the brain produces changes like those seen in Alzheimer’s disease
Previous research has implicated fungi in chronic neurodegenerative conditions such as Alzheimer’s disease, but there is limited understanding of how these common microbes could be involved in the development of these conditions.
Working with animal models, researchers at Baylor College of Medicine and collaborating institutions discovered how the fungus Candida albicans enters the brain, activates two separate mechanisms in brain cells that promote its clearance, and, important for the understanding of Alzheimer’s disease development, generates amyloid beta (Ab)-like peptides, toxic protein fragments from the amyloid precursor protein that are considered to be at the center of the development of Alzheimer’s disease. The study appears in the journal Cell Reports.
“Our lab has years of experience studying fungi, so we embarked on the study of the connection between C. albicans and Alzheimer's disease in animal models,” said corresponding author Dr. David Corry, Fulbright Endowed Chair in Pathology and professor of pathology and immunology and medicine at Baylor. He also is a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “In 2019, we reported that C. albicans does get into the brain where it produces changes that are very similar to what is seen in Alzheimer’s disease. The current study extends that work to understand the molecular mechanisms.”
“Our first question was, how does C. albicans enter the brain? We found that C. albicans produces enzymes called secreted aspartic proteases (Saps) that breakdown the blood-brain barrier, giving the fungus access to the brain where it causes damage,” said first author Dr. Yifan Wu, postdoctoral scientist in pediatrics working in the Corry lab.
Next, the researchers asked, how is the fungus effectively cleared from the brain? Corry and his colleagues had previously shown that a C. albicans brain infection is fully resolved in otherwise healthy mice after 10 days. In this study, they reported that this occurred thanks to two mechanisms triggered by the fungus in brain cells called microglia.
“The same Saps that the fungus uses to break the blood-brain barrier also break down the amyloid precursor protein into AB-like peptides,” Wu said. “These peptides activate microglial brain cells via a cell surface receptor called Toll-like receptor 4, which keeps the fungi load low in the brain, but does not clear the infection.”
C. albicans also produces a protein called candidalysin that also binds to microglia via a different receptor, CD11b. “Candidalysin-mediated activation of microglia is essential for clearance of Candida in the brain,” Wu said. “If we take away this pathway, fungi are no longer effectively cleared in the brain.”
“This work potentially contributes an important new piece of the puzzle regarding the development of Alzheimer’s disease,” Corry said. “The current explanation for this condition is that it is mostly the result of the accumulation of toxic Ab-like peptides in the brain that leads to neurodegeneration. The dominant thinking is that these peptides are produced endogenously, our own brain proteases break down the amyloid precursor proteins generating the toxic Ab peptides.”
Here, the researchers show that the Ab-like peptides also can be generated from a different source – C. albicans. This common fungus, which has been detected in the brains of people with Alzheimer’s disease and other chronic neurodegenerative disorders, has its own set of proteases that can generate the same Ab-like peptides the brain can generate endogenously.
“We propose that the brain Ab-peptide aggregates that characterize multiple Candida-associated neurodegenerative conditions including Alzheimer’s disease, Parkinson’s disease and others, may be generated both intrinsically by the brain and by C. albicans,” Corry said. “These findings in animal models support conducting further studies to evaluate the role of C. albicans in the development of Alzheimer’s disease in people, which can potentially lead to innovative therapeutic strategies.”
For a complete list of the contributors to this work, their affiliations and the financial support for this project, see the publication.
SCIENTISTS DISCOVER LINKS BETWEEN ALZHEIMER’S DISEASE AND GUT MICROBIOTA. PICTURED ARE DR STEFANIE GRABRUCKER AND PROFESSOR YVONNE NOLAN. IMAGE CREDIT: UCC.
Researchers have discovered the link between the gut microbiota and Alzheimer’s disease.
For the first time, researchers have found that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming its role in the disease.
The research was led by Professor Yvonne Nolan, APC Microbiome Ireland, a world leading SFI funded research centre based at University College Cork (UCC), and the Department of Anatomy and Neuroscience, UCC, with Professor Sandrine Thuret at King’s College London and Dr Annamaria Cattaneo IRCCS Fatebenefratelli, Italy.
The study supports the emergence of the gut microbiome as a key target for investigation in Alzheimer’s disease due to its particular susceptibility to lifestyle and environmental influences.
Published in Brain, the study shows that that the memory impairments in people with Alzheimer’s could be transferred to young animals through transplant of gut microbiota.
Alzheimer’s patients had a higher abundance of inflammation-promoting bacteria in faecal samples, and these changes were directly associated with their cognitive status.
Professor Yvonne Nolan said: “The memory tests we investigated rely on the growth of new nerve cells in the hippocampus region of the brain. We saw that animals with gut bacteria from people with Alzheimer’s produced fewer new nerve cells and had impaired memory.”
“People with Alzheimer’s are typically diagnosed at or after the onset of cognitive symptoms, which may be too late, at least for current therapeutic approaches. Understanding the role of gut microbes during prodromal – or early stage- dementia, before the potential onset of symptoms may open avenues for new therapy development, or even individualised intervention,” said Professor Nolan.
Alzheimer's is the most common cause of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life. As our population ages, one in three people born today are likely to develop Alzheimer’s. Funded by Science Foundation Ireland, scientists in UCC are working to develop strategies to promote healthy brain ageing and advance treatments for Alzheimer’s by exploring how the gut microbiota respond to lifestyle influences like diet and exercise.
Professor Sandrine Thuret, Professor of Neuroscience at King’s College London and one of the study’s senior authors said, “Alzheimer’s is an insidious condition that there is yet no effective treatment for. This study represents an important step forward in our understanding of the disease, confirming that the make-up of our gut microbiota has a causal role in the development of the disease. This collaborative research has laid the groundwork for future research into this area, and my hope is that it will lead to potential advances in therapeutic interventions.”
The research was conducted by Dr Stefanie Grabrucker, a postdoctoral researcher working with Professor Nolan, in partnership with postdoctoral colleagues Dr Edina Silajdzic at King’s College London and Dr Moira Marizzoni, IRCCS Fatebenefratelli, Italy. UCC collaborators were Professor Cora O’Neill, Dr Olivia O’Leary, Dr Sarah Nicolas, Dr Jane English, Mr Sebastian Dohm-Hansen and Dr Aonghus Lavelle.
Professor. John F. Cryan, UCC Vice President for Research and Innovation, who was also involved in this research said: “I’m delighted to be involved in this exciting study that further enhances our understanding of the significant role played by the gut microbiome in brain related diseases, such as Alzheimer’s, and recognises UCC and APC Microbiome Ireland as leading institutions in microbiome and brain health research. This research aligns with our UCC Futures Framework and the strategic plan for the University in the areas of Food, Microbiome and Health and the soon to be launched Future Ageing and Brain Science.”
Alzheimer’s disease disproportionately affects women, who represent about two-thirds of those diagnosed with the late-onset type of the disease.
Previous research has shown Alzheimer’s is also more severe and progresses more rapidly in women, and women with Alzheimer’s experience a steeper cognitive decline – loss of memory, attention, and the ability to communicate and make decisions – compared to men with the disease.
The biological bases for these differences between men and women with Alzheimer’s disease are not well understood. However, understanding them is necessary for developing appropriate therapies.
In a new study in mice and humans, Western University researchers have shown female sex hormones play a significant role in how Alzheimer’s manifests in the brain.
The study, published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, also highlights the importance of developing therapeutic strategies focused on these hormonal connections. The research indicates a need to better understand the role of estradiol – a form of the female sex hormone estrogen, used therapeutically to mitigate menopause symptoms – in Alzheimer’s disease.
While the significance of the findings is paramount, the methodology behind them is equally critical, pointing to a necessary shift in scientific approaches.
“To understand how sex hormones play a role in Alzheimer’s, we need to study appropriate animal models. Unfortunately, most studies at this level still focus mainly on the male brain. Our research emphasizes the importance of using animal models that reflect, for instance, postmenopausal women, to understand how sex hormones influence Alzheimer’s pathology,” said Vania Prado, professor, departments of physiology and pharmacology and anatomy & cell biology at Schulich School of Medicine & Dentistry and scientist at Robarts Research Institute.
This study was led by graduate student Liliana German-Castelan, under the supervision of Vania Prado.
Alzheimer’s and the communication system of the brain
One of the key markers of Alzheimer’s disease is the toxic build-up of the protein beta-amyloid in the brain, which eventually disrupts the brain’s communications system and impacts cognition.
The new study shows that the brain chemistry of male and female mice regulates beta-amyloid protein in Alzheimer’s in different ways, with the hormone estradiol contributing to this variation.
Previous studies on mice and at-risk older individuals have revealed that cholinergic neurons, a type of brain cells that produce the chemical messenger acetylcholine, are particularly vulnerable to the damaging Alzheimer’s-associated beta-amyloid accumulation in the brain. Additionally, acetylcholine has been shown to be essential for normal memory and cognition.
While beta-amyloid aggregation impacts the production of acetylcholine, the subsequent loss of this chemical messenger further increases Alzheimer’s pathology, creating a vicious loop.
The team of Western researchers studied this interaction between changes in brain chemistry and the beta-amyloid protein build-up seen in brains impacted by Alzheimer’s.
“Since male and female brains have differences in the cholinergic system, we wanted to see if sex affects this relationship between acetylcholine signalling and the beta-amyloid protein buildup,” said Marco Prado, professor, departments of physiology and pharmacology and anatomy and cell biology. Marco Prado, one of the authors of the study, is also the Canada Research Chair in Neurochemistry of Dementia and a scientist at Robarts Research Institute.
From bench to real-world: representation of sexes matters
In this study, the researchers observed differences in beta-amyloid accumulation in male and female mice when changing the levels of cholinergic activity. Additionally, they analyzed brain MRI images of healthy older humans.
Different from most studies in humans, in which the MRI scans of man and women are analyzed together, Western professor Taylor Schmitz and graduate student Hayley Shanks analyzed MRI brain scans and the rate of brain loss for aged men and women independently.
“We observed that the relationship between the integrity of the brain region where cholinergic neurons reside and beta-amyloid accumulation was the same for men and women but was different in male and female mice,” said Marco Prado. The researchers suspected that the fact the female mice being studied were not post-menopausal, while women were, could be an attributing factor to the difference.
The lead author of the study, German-Castelan, intrigued by the sex differences, decided to introduce another layer of testing into the mouse models and with the help of Western researcher Robert Gros studied female mice who were closely modelled to represent postmenopausal women. This was done to investigate how the presence or lack of sex hormones could impact the relationship between cholinergic signalling and the beta-amyloid buildup in the brain.
“We found that when the sex hormone estradiol was present, the relationship between acetylcholine and toxic amyloid was lost, but when sex hormones were eliminated in the female mice that relationship reproduced the results seen in humans,” said German-Castelan.
These findings also point to the urgent need to study amyloid and cholinergic function in the ‘peri-menopausal’ age range of 40-50 years, which is much younger than the individuals examined in most large-scale studies of Alzheimer’s disease. Indeed, the sample examined in this study were closer to the age of 70 on average.
“Which explains why there were differences between the results of male and female mice and men and women in our initial exploration,” said German-Castelan.
Researchers emphasized that if they hadn't included female mice in the study, they might have missed crucial information about Alzheimer's and sex differences.
“Women and men respond differently to medications and have a somewhat different journey in Alzheimer’s. To develop more effective therapeutics, we need to study animal models that can reproduce different aspects of the journey. Sex hormones and estradiol levels are just one of these factors,” said Vania Prado.
Other authors on the study include Western researchers Lisa M. Saksida and Timothy J. Bussey, and Takashi Saito and Takaomi C. Saido of RIKEN Center for Brain Science, Japan
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