# Antifungal activity of amyloid beta as a driver of dementia and AD pathogenesis.

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2023 · $374,221

## Abstract

PROJECT ABSTRACT
 The blood-brain barrier (BBB) is a highly-restrictive structure that protects the central nervous system
(CNS). Few fungal pathogens, such as Cryptococcus neoformans (Cn), can breach the BBB and invade the
CNS. Fungal spores are prevalent in our environment and we become infected following inhalation of
aerosolized spores. Once inhaled, spores of Cn proliferate in lung tissue and disseminate to the CNS due to
their neurotropic nature. Cn is the leading cause of fungal meningoencephalitis in adults and it is often
misdiagnosed as Alzheimer’s Disease (AD) due to similar neurological symptoms. Indeed, cognitive
impairment was reported in 61% of subjects at least one year following Cn infection diagnosis. In AD,
inflammatory and infectious processes promote BBB dysfunction underscoring the potentially critical role of
the amyloid precursor protein (APP) in endothelial inflammation of the BBB and its subsequent dysfunction.
We resolved the transcriptional signature of human brain microvascular endothelial cells (BMECs) infected
with Cn. BMECs challenged with Cn showed significant dysregulation of several genes essential to the proper
function of the brain endothelium (i.e. BBB), including EphA2-receptor tyrosine kinase, a key mediator of BBB
dysfunction during Cn challenge (based on studies from our parent grant). We also identified APBB3 (amyloid
beta precursor binding protein 3) as a potential mediator of BBB dysfunction. APBB3 is an uncharacterized
protein whose role in APP processing/regulation has never been examined. Our results are consistent with
similar changes reported in the abnormal BBB in AD pathogenesis. Reduced BBB integrity is associated with
neuroinflammation, neuronal injury, oxidative stress and faulty clearance of amyloid beta (A). Based on our
data we propose that fungal brain infection causes BBB dysfunction in part by dysregulating APP and reducing
A clearance which would further damage the BBB. Our data are consistent with recent reports that found
various brain regions from AD patients at autopsy infected with different species of fungi. Fungal DNA,
proteins and structures were identified in frozen brain tissue from AD patients, but not from control patient
tissue. Moreover fungal material was detected intra- and extracellularly in neurons from AD patients. Chitin
polysaccharides, a key component of fungal cell walls, were also identified and human AD cerebral spinal
fluid samples further confirmed the presence of fungi, including Cryptococcus and Candida. Indeed, following
these recent discoveries, and the proposed antimicrobial properties of A a new AD hypothesis referred to
as “antimicrobial protection hypothesis” has emerged. This hypothesis suggests that deposition of A plaque
in brain can initiate early innate immune responses, where A entraps and neutralizes the invading fungal
pathogen under normal conditions. The proposed supplement research project will address 2 specific aims
that are an exte...

## Key facts

- **NIH application ID:** 10711875
- **Project number:** 3R01NS110800-04S2
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** ANGIE GELLI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $374,221
- **Award type:** 3
- **Project period:** 2020-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10711875

## Citation

> US National Institutes of Health, RePORTER application 10711875, Antifungal activity of amyloid beta as a driver of dementia and AD pathogenesis. (3R01NS110800-04S2). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10711875. Licensed CC0.

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