May 19, 2024

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Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer’s Disease

Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer’s Disease



Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer’s Disease

Among hundreds of pathogenic fungi affecting humans, Candida albicans is one of the most common fungal pathogens.

Candida albicans is widely present on the skin and mucous membranes of the human body, being a member of the human symbiotic microbiome. However, when the immune system is compromised, Candida albicans can wreak havoc, causing conditions such as oral ulcers, bloodstream infections, and even penetrating the blood-brain barrier, leading to fungal encephalitis.

Simultaneously, researchers have detected Candida albicans in the brains of patients with Alzheimer’s disease (AD) and other chronic neurodegenerative diseases. Interestingly, patients did not exhibit typical acute disease characteristics, such as fever, rapid changes in mental state, headaches, or increased white blood cell count, suggesting that Candida albicans invading the brain does not elicit the same immune response as other fungal invasions.

A study from 2019 indicated that Candida albicans invasion of the brain induces changes very similar to those observed in AD.

However, in healthy mice infected with acute, low-grade Candida albicans, the infection resolved on its own within 10 days.

Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer's Disease

Therefore, what is the mechanism behind Candida albicans breaking through the blood-brain barrier and being autonomously cleared by the brain?

Building on previous research, scholars at Baylor College of Medicine explored further and discovered that the aspartic proteinase (Saps) produced by Candida albicans is responsible for disrupting the tight junction proteins of the blood-brain barrier, allowing the fungus to enter the brain. After invading the brain, Saps breaks down precursor proteins into Aβ-like peptides. Additionally, Candida albicans secretes a hemolysin, which, together with Saps, activates microglial cells, promoting the brain’s clearance of Candida albicans.

The study was published in Cell Reports.

Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer's Disease

Firstly, the destructive effect of Candida albicans on the blood-brain barrier is undeniable, and tight junction proteins constitute a significant portion of the barrier’s integrity. Researchers found that Saps produced by Candida albicans can hydrolyze most human proteins, with Sap2 being the most efficient in degrading tight junction proteins. In the absence of Sap2, Candida albicans cannot invade the brain.

Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer's Disease

Saps mediate Candida albicans invasion of the brain

Previous studies demonstrated that Candida albicans invasion of the brain produces Aβ-like peptides and activates microglial cells to resist fungal invasion. The researchers then discussed whether Saps would induce the formation of Aβ-like peptides.

Exposed to Saps, mouse neural cells expressing precursor proteins accumulated Aβ-like peptides significantly, while precursor proteins decreased markedly. Fluorescently labeled Saps also revealed marked Aβ-like peptide accumulation in mouse brain slices. Both in vivo and in vitro, Saps secreted by Candida albicans could break down precursor proteins into Aβ-like peptides.

Antifungal experiments suggested that Aβ enhances the antifungal activity of microglial cells in a TLR4-dependent manner. Intravenous injection of Candida albicans cells into mice showed that the fungal burden in the brains of TLR4-deficient mice was significantly higher than in wild-type mice.

Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer's Disease

Aβ enhances the antimicrobial activity of BV-2 cells by binding to TLR4

However, the researchers also found in experiments that relying solely on the binding of Aβ-like peptides to TLR4 is not sufficient to induce microglial cells to clear all Candida albicans.

Considering the crucial role that hemolysin plays in driving immune responses in other infections, the researchers injected mice with hemolysin-deficient Candida albicans.

They found that the efficiency of deficient cells entering the brain was twice that of wild-type cells, and the brain’s clearance efficiency of Candida albicans was significantly reduced, extending from 10 days to 60 days.

CD11b is the receptor for fungal proteinase cleavage of fibrinogen and is also a highly expressed heterodimer integrin on microglial cells. Inhibiting CD11b activity, preventing CD11b from binding to hemolysin, affects the ability of microglial cells to clear Candida albicans. CD11b-deficient mice showed reduced efficiency in clearing Candida albicans, similar to mice infected with hemolysin-deficient Candida albicans.

Despite Candida albicans being one of the most common human pathogens, we have finally uncovered the secrets of how it disrupts the blood-brain barrier and the innate antifungal immunity of the brain today—Aβ-like peptides binding to TLR4 and hemolysin binding to CD11b both enhance the ability of microglial cells to clear Candida albicans.

However, even with these robust antifungal pathways, Candida albicans can persist in multiple organs. Understanding the long-term threat that Candida albicans poses to human health and its potential role in neurological diseases remains an urgent issue for us to address.

Fungal Disruption of Blood-Brain Barrier: Triggering Alzheimer’s Disease

References:

[1] Wu Y, Du S, Johnson J L, et al. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits[J]. Nature communications, 2019, 10(1): 58.

[2] Wu Y, Du S, Bimler L H, et al. Toll-like receptor 4 and CD11b expressed on microglia coordinate eradication of Candida albicans cerebral mycosis[J]. Cell Reports, 2023, 42(10).

(source:internet, reference only)


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