Brain fungi have previously been linked to chronic neurodegenerative disorders such as Alzheimer’s disease, but there is still a lack of understanding of how these widespread bacteria can contribute to the development of these conditions.
Using animal models, Baylor College of Medicine and collaborators discovered how the fungus Candida albicans enters the brain, activates two distinct mechanisms in brain cells that promote its clearance, and, crucially for understanding Alzheimer’s disease development, generates amyloid beta (Ab)-like peptides, toxic protein fragments from the amyloid precursor protein that are thought to be at the center of the disease’s development. The findings were published 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,” explained corresponding author Dr. David Corry, Fulbright Endowed Chair in Pathology and professor of pathology, immunology, and medicine at Baylor. He is also affiliated with Baylor’s Dan L Duncan Comprehensive Cancer Center. “In 2019, we reported that C. albicans enters the brain and causes changes that are very similar to those seen in Alzheimer’s disease.” The current study expands on prior work in order to better understand the molecular pathways.”
“Our first question was how C. albicans gets into the brain.” “We discovered that C. albicans produces enzymes called secreted aspartic proteases (Saps) that break down the blood-brain barrier, allowing the fungus to enter the brain and cause damage,” stated first author Dr. Yifan Wu, a pediatric postdoctoral investigator in the Corry lab.
The researchers then inquired as to how the fungus is properly removed from the brain. Corry and his colleagues recently demonstrated that a C. albicans brain infection resolves completely in otherwise healthy rats after 10 days. They found in this study that this occurred as a result of two mechanisms induced 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,” he 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.
Candida albicans also produces candidalysin, a protein that interacts to microglia via a separate receptor, CD11b. “Candidalysin-mediated activation of microglia is essential for clearance of Candida in the brain,” he stated. “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,” he stated. “The current explanation for this condition is that it is primarily the result of toxic Ab-like peptide accumulation in the brain, which leads to neurodegeneration.” The prevalent belief is that these peptides are created endogenously, that our own brain proteases degrade the amyloid precursor proteins, resulting in the poisonous Ab peptides.”
The researchers demonstrate that Ab-like peptides can be produced from a different source – Candida albicans. This common fungus, which has been found in the brains of persons suffering from Alzheimer’s disease and other chronic neurodegenerative illnesses, has its own set of proteases capable of producing the same Ab-like peptides that the brain produces 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,” he added. “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.”
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