Active Brain & Nervous System Infection & Immunity

Investigating the response of human microglia to amyloid beta in an in vitro tri-culture model of neuroinflammation

Funder Wellcome Charity-funded
Recipient organisation University of Dundee
Funding Not disclosed
Period Oct 2025 — Sept 2028

In plain English

AI plain-English summary

Microglia, the brain’s immune cells, stop clearing toxic amyloid beta protein in Alzheimer’s disease, and this project will watch that failure happen in a dish using human cells grown in brain-like proportions. This matters because Alzheimer’s is the leading cause of dementia—responsible for more than one in 10 UK deaths in 2023—and two-thirds of patients are female, a sex difference with no clear explanation. Current models rely on animal cells or simplified cultures that miss the three-way conversation between microglia, neurons, and astrocytes. By co-culturing human stem-cell-derived versions of all three cell types, the researcher can observe how microglia lose their clean-up function and turn proinflammatory. The platform also uses sex-matched cell lines from a donor with Klinefelter’s syndrome (XXY chromosomes) to test whether cellular responses to amyloid differ by sex. This is fundamental science. It will not produce a drug or diagnostic tomorrow. But understanding the cellular mechanics of microglial failure—and why women are disproportionately affected—could eventually point to new targets for therapies that restore the brain’s own waste-disposal system, rather than just clearing plaques after they form.

View original technical description
Dementia is a leading cause of death, responsible for more than one in 10 UK deaths in 2023. Alzheimer’s disease is the leading cause of dementias, and presents a significant social and medical challenge, especially in the context of nations with aging populations and inadequate memory care resources. Alzheimer's disease is extremely complex in its aetiology and difficult to research. Additionally, there is an as-yet-unexplained sex difference in incidence, with 2/3 of patients being female. A characteristic element of its pathophysiology- and therefore a target for study- is the presence of amyloid plaques, aggregations of amyloid beta protein that form first in the neocortex and are gradually found in deeper areas of the brain as the disease progresses. Normally, amyloid is phagocytosed by microglia, brain-resident immune cells. In Alzheimer's, microglia lose this function, polarising towards a more proinflammatory phenotype. My project aims to investigate the cellular- level changes behind this change in function, using human IPSC-derived microglia, neurons and astrocytes cocultured in brain-like ratios. This will then be a base platform for amyloidosis experiments. We will also interrogate cellular-level sex differences in response to amyloid, using sex-matched IPSC lines from a donor with Klinefelter’s syndrome and the original chromosomes XXY.

View the original record at the funder ↗

Researchers

Tera Birchall (EPMC Awardee)

Related Research

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"Investigating Microglial-Dependent Mechanisms of Amyloid-Beta Toxicity Using a Novel Mouse Model"
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Original classification

PhD Studentship (Basic)

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