Studying Microglia-Mediated Neurodegeneration Using Cocultures
type: CreativeWork
description: Microglia are resident innate immune cells of the central nervous system with potent phagocytic and inflammatory capabilities. These cells are crucial in both health and disease, including neurodegenerative diseases. Genetics studies have linked Alzheimer’s disease and other diseases to genes that affect microglial functions, and evidence indicates that microglial phagocytosis and inflammation control neuronal function and survival. Some microglial activity may be beneficial during neurodegeneration, but excessive release of pro-inflammatory cytokines and reactive oxygen/nitrogen species is a hallmark of neurodegenerative disease and can promote neurodegeneration. Additionally, microglial phagocytosis of the protein aggregates driving proteinopathic diseases may be beneficial, but excessive microglial phagocytosis of synapses or neurons may contribute to neurodegeneration. Overall, study of microglia-mediated neurodegeneration is essential when working towards microglia-targeted therapies for dementias, such as Alzheimer’s disease, and other conditions. In order to study these interactions between microglia and neurons, *in vitro* model systems are required that include both cell types. Use of these models has often been limited to low-throughput experiments due to practical challenges and the need for careful manual analysis of individual cell types. In this work, I used a neuron-glia coculture model in which inflammatory activation of microglia with lipopolysaccharide (LPS) or other stimuli results in neuronal loss, addressing the above limitations by building an imaging and analysis workflow using recent methods and machine learning tools. This enabled accurate, automated analysis of images from primary cocultures. Early tests of these higher-throughput assays identified potential roles for urokinase (uPA) and spleen tyrosine kinase (SYK) in microglia-mediated neurodegeneration. uPA is an extracellular protease that may also regulate migration, inflammation and p…
abstract: Microglia are resident innate immune cells of the central nervous system with potent phagocytic and inflammatory capabilities. These cells are crucial in both health and disease, including neurodegenerative diseases. Genetics studies have linked Alzheimer’s disease and other diseases to genes that affect microglial functions, and evidence indicates that microglial phagocytosis and inflammation control neuronal function and survival. Some microglial activity may be beneficial during neurodegeneration, but excessive release of pro-inflammatory cytokines and reactive oxygen/nitrogen species is a hallmark of neurodegenerative disease and can promote neurodegeneration. Additionally, microglial phagocytosis of the protein aggregates driving proteinopathic diseases may be beneficial, but excessive microglial phagocytosis of synapses or neurons may contribute to neurodegeneration. Overall, study of microglia-mediated neurodegeneration is essential when working towards microglia-targeted therapies for dementias, such as Alzheimer’s disease, and other conditions. In order to study these interactions between microglia and neurons, *in vitro* model systems are required that include both cell types. Use of these models has often been limited to low-throughput experiments due to practical challenges and the need for careful manual analysis of individual cell types. In this work, I used a neuron-glia coculture model in which inflammatory activation of microglia with lipopolysaccharide (LPS) or other stimuli results in neuronal loss, addressing the above limitations by building an imaging and analysis workflow using recent methods and machine learning tools. This enabled accurate, automated analysis of images from primary cocultures. Early tests of these higher-throughput assays identified potential roles for urokinase (uPA) and spleen tyrosine kinase (SYK) in microglia-mediated neurodegeneration. uPA is an extracellular protease that may also regulate migration, inflammation and p…
author: Birkle, Timothy
language: eng
keywords: Biology, Cocultures, Inflammation, Microglia, Neurobiology, Neurodegeneration, Neuroinflammation, Screening
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/cd2ee8f6-2e37-482a-84df-6c8b4fda373c/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-11-03
date modified: 2026-07-22T22:24:03Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.107480