Establishing the role of fungal infection in potentiating Alzheimer’s Disease risk

Summary

Low-level microbial infection of the brain is understood to have an impact on the development or severity of Alzheimer’s disease. Cryptococcus neoformans is an environmental fungus known to infect the brain and cause potentially lethal meningitis in immunocompromised individuals. We hope to establish if C. neoformans can trigger Alzheimer’s-related processes and if it is found at higher levels in the brains of Alzheimer’s patients compared to healthy individuals.

What are we doing?

Although the pathology of Alzheimer’s Disease has been well described, the contributing triggers remain unclear. Drug development focuses on reducing symptoms rather than preventing the disease altogether, so we’re hoping to identify a new trigger to help inform preventative treatments.

How are we doing it?

We’ll explore how infection with C. neoformans can cause Alzheimer’s-associated genetic and functional changes in the primary immune cell of the brain: microglia. We’ll aim to do this by investigating if infection:

• Increases the expression of Alzheimer’s-associated genes in microglia.
• Induces epigenetic (regulatory) changes in these genes.
• Impairs microglial clearance of Alzheimer’s proteins and cell debris.

Clinical brain samples will also be used to look for higher levels of C. neoformans in the Alzheimer’s brain compared to heathy individuals. Initially, cell cultures of microglia infected with C. neoformans will be used as a model. The techniques likely to be utilized include RT-qPCR, phagocytosis assays, viability assays, and microscopy. Following these, I will use PCR and antigen detection to assess fungal levels in Alzheimer’s and healthy brain tissue, and also potentially identify any changes observed in cell culture.

What happens next?

Depending what is shown, the results of this PhD could inform several areas of research:

• Exploration into specific molecular targets, identified from genetic data, in the pathogenesis of Alzheimer’s disease.
• Use of anti-fungal and other anti-microbial treatments in the prevention of Alzheimer’s Disease.
• Application to the development and treatment of cryptococcal meningitis.

Supervisors

Dr Liz Ballou (Primary)

Dr Jonathon Witton (Secondary)

Dr Katie Lunnon (Secondary)