Common type of fungus can invade the mammal brain and induce the formation of toxic amyloid plaques, similar to Alzheimer’s disease.
The research, conducted on mice, suggests a potential external source for a key characteristic of some neurodegenerative diseases.
Previously, amyloid protein clumps accumulating between neurons were attributed solely to internal factors like stress or inflammation within the brain.
However, scientists have increasingly found signs of a common fungus, Candida albicans, in the brains of individuals who died with Alzheimer’s and other neurodegenerative conditions like Parkinson’s.
This raises the possibility that external infections can breach the mammal brain and trigger an innate immune response. While this response aims to eliminate pathogens, it may also lead to Alzheimer’s-like symptoms if not properly regulated.
To investigate this further, an international research team led by Baylor College of Medicine in the United States utilized a mouse model.
Prior research by the same Baylor lab demonstrated memory decline in mice infected with C. albicans, which then reversed upon clearing the fungal infection.
What’s in the Study?
First, C. albicans was injected directly into the brains of mice. Four days later, the mice were put down and their brains were analyzed further.
Several slices of brain tissue were imaged, and some cells were cultured in dishes.
The findings suggest that once inside the brain, C. albicans may trigger two neuroimmune mechanisms. One mechanism is thought to activate immune cells that suppress the fungus, and another is believed to trigger them into removing the intruder altogether.
The first mechanism involves a fungal enzyme called Saps, which is thought to make the protective barrier between the bloodstream and the brain more leaky. This allows any fungal cells that may be flowing through the body’s bloodstream to enter the brain.
At the same time, Saps is also believed to break apart proteins similar to amyloid beta, the protein that forms plaques in Alzheimer’s brains. This, in turn, is believed to trigger immune cells responsible for clearing debris called microglia.
The second mechanism involves another secreted substance by the fungus, which is also believed to trigger microglia, this time into targeting the fungus for removal.
Together, both immune pathways have been shown to be effective in combating acute C. albicans infections in healthy mouse brains, typically doing so in about 10 days.
But not all brains are young and healthy. When researchers purposefully disrupted the microglia response in mouse brains, they found that C. albicans infections were significantly extended.
“This pathway is believed to be crucial for clearing fungus from the brain.”
Yifan Wu from Baylor College of Medicine
A new hypothesis proposes that the amyloid beta-like clumps observed in mouse brains might act as a defense mechanism against invading pathogens. However, if these clumps aren’t effectively cleared by microglia, their lingering presence could potentially cause harm over time.
While this is currently just a theory, it aligns with recent findings suggesting amyloid beta plaques appear later in Alzheimer’s disease, not as the initial trigger for cognitive decline. This could explain the limited success of treatments targeting these plaques in humans.
“This research has the potential to contribute a significant new piece to the puzzle of Alzheimer’s disease development.”
David Corry
“The prevailing belief is that these peptides are produced internally; our brain’s proteases break down amyloid precursor proteins, generating the toxic amyloid beta peptides.”
However, this new study suggests otherwise.
Significantly more research is needed, both using living animal models and human cells. However, the Baylor researchers are optimistic that their initial experiments could pave the way for innovative future therapies for cognitive decline.
https://doi.org/10.1016/j.celrep.2023.113240
Abstract
The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer’s disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. Recognition of Aβ-like peptides and candidalysin promotes fungal clearance from the brain, and disruption of candidalysin recognition through CD11b markedly prolongs C. albicans cerebral mycosis. Thus, C. albicans is cleared from the brain through innate immune mechanisms involving Saps, Aβ, candidalysin, and CD11b.