More than 6 million Americans are living with Alzheimer's. By 2050, this number is projected to rise to nearly 13 million. (© Orawan - stock.adobe.com)
HOUSTON — A troubling new study shows a link between a common fungus and Alzheimer’s disease. Scientists from the Baylor College of Medicine are revealing how the fungus Candida albicans enters the brain, triggers mechanisms that aid in its clearance, and generates toxic protein fragments known as amyloid beta (Ab)-like peptides — a key player in Alzheimer’s disease development.
“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 study corresponding author Dr. David Corry, the Fulbright Endowed Chair in Pathology and a professor of pathology and immunology and medicine at Baylor, in a university release. “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.”
The study first sought to unravel how Candida albicans gains access to the brain. Researchers discovered that the fungus produces enzymes called secreted aspartic proteases (Saps), which break down the blood-brain barrier — a protective barrier that usually prevents harmful substances from entering the brain. This breach allows the fungus to infiltrate the brain and cause damage.
The next question posed by the researchers was how the brain effectively clears the fungus. Previous research has shown that C. albicans brain infections resolve entirely in healthy mice after 10 days. In this study, the team unveiled two mechanisms triggered by the fungus in microglia brain cells, which play a crucial role in the brain’s immune response.
“The same Saps that the fungus uses to break the blood-brain barrier also break down the amyloid precursor protein into Ab-like peptides,” says study first author Dr. Yifan Wu, postdoctoral scientist in pediatrics working in the Corry lab. “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.”
Additionally, C. albicans produces a protein called candidalysin that binds to microglia via a different receptor, CD11b.
“Candidalysin-mediated activation of microglia is essential for clearance of Candida in the brain,” notes Dr. Wu. “If we take away this pathway, fungi are no longer effectively cleared in the brain.”
The implications of this research extend to the understanding of Alzheimer’s disease development. The prevalent theory suggests that Alzheimer’s is primarily driven by the accumulation of toxic Ab-like peptides in the brain, leading to neurodegeneration. These peptides are believed to be produced endogenously within the brain.
However, the current study reveals an alternative source for these Ab-like peptides — C. albicans. This common fungus, previously detected in the brains of individuals with Alzheimer’s disease and other chronic neurodegenerative disorders, possesses its own set of proteases that can generate the same Ab-like peptides produced within the brain itself.
“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,” explains Dr. Corry. “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.”
The study is published in the journal Cell Reports.
