Common Fungus Triggers Alzheimer’s-Like Changes in Mouse Brain
A common fungus produces Alzheimer’s-disease like changes in mouse brains. A new study has determined how these molecular changes occur.
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C. albicans – a common fungus – can enter the mouse brain
In 2019, the laboratory of Dr. David Corry, Fulbright Endowed Chair in Pathology and professor of pathology and immunology and medicine at Baylor College of Medicine, published a paper demonstrating that the common fungus Candida albicans (C. albicans) can enter the mouse brain. “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,” says Corry.
In the mouse brain, C. albicans caused physiological changes that are similar to the pathology of Alzheimer’s disease, notably the accumulation of toxic amyloid beta (AB)-like peptides. How the fungal pathogen triggers these molecular changes was, at that point, unknown. Corry’s latest research, published in Cell Reports extends the 2019 study to provide some answers.
C. albicans uses Saps to break down the blood–brain barrier
The team’s first task was to decipher how C. albicans enters the brain in the first place. “We found that C. albicans produces enzymes called secreted aspartic proteases (Saps) that break down the blood–brain barrier, giving the fungus access to the brain where it causes damage,” says Dr. Yifan Wu, postdoctoral scientist in pediatrics working in the Corry lab, and first author of the paper. Saps are produced by several different types of microorganisms, and studies have demonstrated that different types of Saps can induce the production of various proinflammatory cytokines in human monocytes, a type of immune cell. In Corry and team’s study, they found that Sap2 is particularly capable of degrading the endothelial junctions and aiding the fungus’ entrance into the brain.
In 2019, Corry and colleagues demonstrated that a C. albicans infection is resolved in healthy mice after a 10-day period. How does the brain effectively clear the fungus? “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 says. “These peptides activate microglial brain cells via a cell surface receptor called Toll-like receptor 4, which keeps the fungal load low in the brain, but does not clear the infection.”
An exogenous source of Ab-like peptides
A protein, candidalysin, secreted by C. albicans is also required to clear the infection. This protein binds to a different microglial receptor, called CD11b. If this pathway is removed in mice, the fungal infection persists.
What does this research mean for our understanding of Alzheimer’s disease, and the proposed theory that fungi might be implicated in its pathogenesis? Corry explains: “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.”
But the team’s work suggests that Ab-like peptides can be produced by other sources, such as C. albicans. The fungus has been detected in the brains of individuals with Alzheimer’s disease, in addition to other neurodegenerative disorders. “This work potentially contributes an important new piece of the puzzle regarding the development of Alzheimer’s disease,” Corry says. “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.”
The research team states that their animal model data warrants further research to assess the role of C. albicans in Alzheimer’s disease in humans, which might lead to a novel understanding of the disease and in turn, new therapeutic strategies.
Reference: Wu Y, Du S, Bimler LH, et al. Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis [published online ahead of print, 2023 Oct 10]. Cell Rep. 2023;42(10):113240. doi: 10.1016/j.celrep.2023.113240
This article is a rework of a press release issued by Baylor College of Medicine. Material has been edited for length and content.