Microglial interactions with neurons in health, ageing and neurodegeneration
Lead Research Organisation:
University of Cambridge
Department Name: Biochemistry
Abstract
Microglia are brain macrophages involved in shaping, protecting and killing brain neurons in development, health, aging and neurodegeneration. Brain inflammation and microglial activation occurs with over-nutrition, aging and neuroinflammation. We have been investigating the mechanisms by which microglia become inflamed and damage neurons. Recently we have found that inflamed microglia can phagocytose (i.e. eat) live neurons, and thereby cause neuronal death and loss, which we have called 'phagoptosis'. Phagoptosis is cell death by phagocytosis of the cell, and thus is prevented by blocking phagocytosis. Phagocytosis of an otherwise-viable cell may occur because the cell is stressed, activated, senescent, damaged, recognised as non-self or misrecognised. And phagoptosis is greatly enhanced during inflammation. This project will be investigating the signals and receptors involved in this process, and whether phagocytosis is beneficial or detrimental in over-nutrition and aging. In particular, we will model over-nutrition and aging in brain cell cultures and hippocampal slice cultures; and test the roles of the phagocytic receptors VNR, MerTK or P2Y6 receptors in neuronal and synaptic loss. We will be testing the hypothesis that blocking these phagocytic receptors prevents neuronal and synaptic loss in over-nutrition and aging, and consequently might be used as therapeutic targets. The project will use cell culture, fluorescence microscopy, immunohistochemistry, Western blotting, molecular cell biology and animal models where appropriate.
Organisations
People |
ORCID iD |
Guy Brown (Primary Supervisor) | |
Thomas Cockram (Student) |
Publications
Allendorf DH
(2020)
Lipopolysaccharide activates microglia via neuraminidase 1 desialylation of Toll-like Receptor 4.
in Journal of neurochemistry
Butler CA
(2021)
Microglial phagocytosis of neurons in neurodegeneration, and its regulation.
in Journal of neurochemistry
Cockram T
(2020)
Microglial Phagocytosis of Bacteria and Synapses
Cockram T
(2021)
The Phagocytic Code Regulating Phagocytosis of Mammalian Cells.
Cockram TOJ
(2021)
The Phagocytic Code Regulating Phagocytosis of Mammalian Cells.
in Frontiers in immunology
Cockram TOJ
(2019)
Calreticulin and Galectin-3 Opsonise Bacteria for Phagocytosis by Microglia.
in Frontiers in immunology
Klaus C
(2021)
Sialylation acts as a checkpoint for innate immune responses in the central nervous system.
in Glia
Puigdellívol M
(2021)
The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration.
in Cell reports
Puigdellívol M
(2020)
Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration.
in Frontiers in cellular neuroscience
Reid KM
(2022)
Brain Cells Release Calreticulin That Attracts and Activates Microglia, and Inhibits Amyloid Beta Aggregation and Neurotoxicity.
in Frontiers in immunology
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
BB/M011194/1 | 30/09/2015 | 31/03/2024 | |||
1645643 | Studentship | BB/M011194/1 | 30/09/2015 | 29/09/2019 | Thomas Cockram |
Description | I have investigated the regulation of microglial phagocytosis in the context of synapses and bacteria. Microglia are brain immune cells responsible for ingesting, or phagocytosing, various targets including cells, cellular debris, pathogenic material (including bacteria), and synapses. In particular, I have identified novel regulators of this phagocytosis using in vitro phagocytosis models with both bacteria and synaptosomes (isolated synapses). |
Exploitation Route | My findings provide a starting point to i. identify drug targets for bacterial infection in the central nervous system ii. further elucidate how synaptic removal in the developing central nervous system is regulated |
Sectors | Pharmaceuticals and Medical Biotechnology |