# Chronic Murine Cerebral Mycosis: Pathogenesis, Neuroimmune Response, and Relevance to Alzheimer's Disease

> **NIH NIH K01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $129,032

## Abstract

Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States and the only cause of death in
the top ten that cannot be effectively prevented, treated, or cured. Recent evidence suggests that AD may be
linked to fungal brain infections. To rigorously study this possibility, we established a model of cerebral mycosis
by intravenously (IV) injecting the pathogenic yeast Candida albicans, which transits the blood brain barrier to
establish a parenchymal brain infection. The resulting cerebral mycosis induces mild memory deficits and fungal
induced glial granulomas (FIGGs) consisting of microglial aggregates, amyloid β (aβ) deposits, and amyloid
precursor protein (APP) surrounding yeast aggregates. This structure essentially duplicates AD’s characteristic
senile plaques, but the cerebral mycosis and memory loss are transient, not persisting beyond 10 days after a
single intravenous infection. In contrast, AD involves numerous senile plaques and tauopathy that presumably
accrue over many years in the setting of chronic cerebral mycosis that is linked to progressive, irreversible
dementia. This raises the key possibility that C. albicans might persist in a remote tissue site, such as the
intestines, from which it might periodically mobilize to chronically re-infect the brain. As both C. albicans
colonization of the GI tract and low-level candidemia deriving from the GI tract have been documented in
humans, we hypothesize that chronic C. albicans enteritis leads to low-level transmission of fungal cells into the
bloodstream and persistent cerebral mycosis. To test this hypothesis and establish a more translationally
relevant chronic model, we administered yeast from C. albicans to wildtype C57BL/6 mice via oral gavage. We
found that live yeast are recoverable from the brain as soon as 2 days post gavage and out to at least day 58
and this persistence is altered in human APOE4 transgene mice, which express the human allele of APOE that
is linked to two-thirds of AD cases. Additionally, these colonies were polymicrobial, consisting of both yeast and
bacteria, an observation that is consistent with recent published analysis and our own cultures of AD brains that
demonstrate polymicrobial brain infections involving both fungi and bacteria. Consistent with our previous IV
model, chronically infected WT mice present with elevated brain aβ 1-40 and 1-42 and both genotypes present
with abnormal behavior. To further determine the potential of this model as a translational model for AD, we
propose the following aims: (1) to determine the histopathological and physiological brain response to
polymicrobial infection, (2) To determine the mechanism of metastasis of gut fungi and bacteria to the brain, (3)
to determine effect of gastric inflammation on metastasis of gut fungi and bacteria to the brain. Through this
study we will establish if this infection produces an AD phenotype, how this infection invades the brain and
persists in the host, and...

## Key facts

- **NIH application ID:** 10888374
- **Project number:** 5K01AG083219-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Lynn Bimler
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $129,032
- **Award type:** 5
- **Project period:** 2023-07-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10888374

## Citation

> US National Institutes of Health, RePORTER application 10888374, Chronic Murine Cerebral Mycosis: Pathogenesis, Neuroimmune Response, and Relevance to Alzheimer's Disease (5K01AG083219-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10888374. Licensed CC0.

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