ALZHEIMER'S DISEASE (AD)
AD involves alterations in immune function that exacerbate the pathologic condition. We study the signaling mechanisms that drive these changes and how they can be corrected using engineering-based approaches.
Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder with a poorly understood etiology and pathophysiology. Additionally, there is a lack of treatments for the condition, and of the few disease-modifying therapies available, their efficacy is limited. One of the hallmarks of AD is the accumulation of amyloid-beta plaques (Aβ) in the extracellular space of the brain. While neuronal degradation is the most ostensible sign of AD, the remaining glial cells in the brain also undergo morphological changes. Our lab specifically investigates microglia, a phagocytic immune cell found in the brain and other nervous tissue. As AD progresses, microglia present with a different phenotype known as disease-associated microglia (DAM). DAMs are, most notably, unable to properly clear amyloid beta, a function they normally perform. Therefore, they are believed to accelerate disease progression. Within this thrust, our lab is focused on two aspects of dysregulation: the role of extracellular-related kinase (ERK) signaling and the role of heme in the dysregulation promoting DAMs.
Systems Analysis of Neuroinflammatory Signaling in AD.
Role of microglia MAPK/ERK signaling in AD
ERK is a subfamily of the mitogen-activated kinase (MAPK) family. MAPKs play a significant role in the immunological profile of microglia. Our research utilizes various methods to probe the role of ERK signaling, including cellular and animal models, alongside computational modeling techniques. Using these approaches, we identify different targets in the signaling pathway and explore the efficacy of molecules that interact with those targets to restore the normal microglia phenotype. This work is done in collaboration with the Rangaraju Lab.
Role of heme signaling in AD
Heme is a cofactor commonly known for its role in oxygen transport and storage. Beyond this role, heme has been shown to possess immunomodulatory properties. Notably, in the brains of AD patients, the immunomodulatory pathways heme acts on are upregulated in microglia. We utilize genetic engineering in cellular models, supplemented with computational modeling to further investigate this role. The aim of this work is to leverage the improved understanding of heme’s function to develop treatments that restore physiologic phenotypes in microglia. This work is done in collaboration with the Reddi Lab.
More information can be found in the articles on the right.
Figure 1. Increased p-ERK1/2 in microglia cells from the 5xFAD AD mouse model. Chen et al. 2021. Journal of Neuroscience Research.
PUBLICATIONS
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Galea, E., Weinstock, L., Larramona, R., Pybus, A., Gimenez-Llort, G., Escartin, C., Wood, L., 2022. Multi-transcriptomic analysis points to early organelle dysfunction in human astrocytes in Alzheimer's disease, Neurobiology of Disease, 166: 105655.
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Chen, J., Ramesha, S., Weinstock, L., Gao, T., Ping, L., Xiao, H., Dammer, E., Duong, D., Levey, A., Lah, J., Seyfried, N. Wood, L., Rangaraju, S., 2021. Extracellular signal-regulated kinase regulates microglial immune responses in Alzheimer’s disease, Journal of Neuroscience Research, 99: 6.
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Sankar, S., Infante-Garcia, C., Weinstock, L., Ramos-Rodriguez, J., Hierro-Bujalance, C., Fernandez-Ponce, C., Wood, L., Garcia-Alloza, M., 2020. Amyloid beta and diabetic pathology cooperatively stimulate cytokine expression in an Alzheimer's mouse model, Journal of Neuroinflammation, 17: 38.
