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Full NameProfessor Maeve Caldwell
- cell and developmental biology/regenerative medicine
- Other
Induced pluripotent stem cells
- Medicine
- Pathology
- Dementia
- Immunology
- Neurology
- Pharmacology
- Physiology
My lab uses human induced pluripotent stem cells (iPSC) to study mechanisms of disease in neurodegeneration, with a specific interest in Parkinson's and Alzheimer’s disease. We can differentiate iPSC into the main cell types in the brain, including astrocytes, neurons and microglia and study how inflammation affects their behaviour and function. We are particularly interested in the role of peripheral immune cells mediated inflammation in glial cells and how that affects neuronal survival. Our lab is the only lab nationally working with human IPSCs to model neurodegeneration. We combine cell biology/cell sorting, molecular biology and histological approaches to tease out disease mechanisms and use our defined populations as models for drug discovery.
Recent publications
1) McComish SF, O'Sullivan J, Copas AMM, Imiolek M, Boyle NT, Crompton LA, Lane JD, Caldwell MA. Reactive astrocytes generated from human iPSC are pro-inflammatory and display altered metabolism. Exp Neurol. 2024 Dec;382:114979. Epub 2024 Sep 30.
2) MacMahon Copas AN, McComish SF, Petrasca A, McCormack R, Ivers D, Stricker A, Fletcher JM, Caldwell MA. CD4+ T cell-associated cytokines induce a chronic pro-inflammatory phenotype in induced pluripotent stem cell-derived midbrain astrocytes. Glia. 2024 Nov;72(11):2142-2154.
Investigating the contribution of APOE4 genotype to glial mediated inflammation in Alzheimer’s disease.
Approximately 90% of cases of Alzheimer’s disease occur sporadically with late onset with less than 10% being due to a familial mutation. It is well established that there are two main pathologies associated with this disease, namely a build up of beta-amyloid plaques and of tau containing neurofibrillary tangles. Interestingly, more than 40 genetic loci have been associated with the increased risk of developing late onset disease and the genes associated with this are often expressed in glial cells including astrocytes and microglia. One such gene is Apolipoprotein E (APOE) which represents a significant fraction of the heritable risk for late onset disease. The human APOE gene encodes one of three isoforms E2, E3 and E4, which differ by just two amino acids, producing substantial isoform specific properties. Different isoforms of APOE modify the risk of disease development. Indeed APOE4 is associated with an increased risk of AD, 5 times for heterozygotes and 14 times for homozygotes compared to carriers of E3 (considered the normal form). In fact greater than 65% of Alzheimer’s disease patients carry a copy of APOE4.
This project will investigate how APOE genotype influences glial responses to peripheral immune cell mediated inflammation and how that effects glutamatergic neuronal survival and function. Indeed inflammation is now thought to be the third pathology associated with Alzheimer’s disease. The model system employed will be human induced pluripotent stem cells which have either an APOE3 or an APOE4 genotype and which will be differentiated into astrocytes, microglia and neurons; working protocols are well established in the lab. This will involve media transfer and co-culture experiments, RNA sequencing, ELISA, FACS and immunohistochemistry. This model will also be used for therapeutic development; to test novel compounds to reduce inflammation.