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Guy Brown

Neuroinflammation, mitochondria and cell death

The lab uses biochemical and cell biology approaches to study mammalian cell physiology and pathology: that is how our cells work and how they go wrong in disease.  Current research focuses on: 

1) Inflammation in brain pathology and neurodegeneration: Brain inflammation may contribute to many brain pathologies, including Alzheimer’s, Parkinson’s, stroke, trauma, infections, and aging.  We have characterized three mechanisms by which inflamed glia can damage neurons: i) NO from inducible NO synthase damaging mitochondria, ii) oxidants from NADPH oxidase mediating activation of microglia, and iii) activated microglia phagocytosing live neurons. 

2) Cell death by phagocytosis, termed 'phagoptosis', is a ‘new’ form of cell death, and we are investigating its mechanisms and role in neurodegeneration, stroke and trauma.

3) Mitochondria in cardiovascular pathology: Heart attacks and heart failure damage the heart via ischaemia (reduced blood flow). We have found that heart ischaemia causes rapid mitochondrial damage and apoptosis, and we are investigating the mechanisms involved and how to prevent this damage.

4) Cell death in leukaemia: We are investigating potential new treatments for leukaemia that induce cell death of leukaemic cells.

5) Nitric oxide (NO), mitochondria and cell death:  We have shown that NO inhibits mitochondrial respiration, which leads to increased production of oxidants, which in turns can lead to inflammation or cell death. We are interested generally in how mitochondria within cells regulate cell functions and cell death.

Lab members:

Anna Vilalta, Tamara Hornik, Lucy Metayer, Koji Nomura, Rachael Stone and Aviva Tolkovsky

Key publications:

Neher JJ, Emmrich JV, Fricker M, Mander PK, Thery C, Brown GC (2013) Phagocytosis executes delayed neuronal death after focal brain ischemia. Proc Natl Acad Sci 110:E4098-107.

Hornik TC, Neniskyte U & Brown GC (2013) Inflammation induces Multinucleation of Microglia via PKC inhibition of Cytokinesis, generating highly phagocytic Multinucleated Giant Cells. J. Neurochem. In press

Emmrich J. Hornik T Neher J & Brown GC (2013) Rotenone induces neuronal death by microglial phagocytosis of neurons. FEBS J. 280, 5030-5038.

Fricker M, Vilalta A, Tolkovsky AM, Brown GC (2013) Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J Biol Chem. 288, 9145-52.

Neniskyte U, Brown GC (2013) Lactadherin/MFG-E8 is essential for microglia-mediated neuronal loss and phagoptosis induced by amyloid β. J Neurochem. 126, 312-7.

Brown GC & Neher JJ (2012) Eaten alive! Cell death by primary phagocytosis: ‘phagoptosis’. Trends Biochem. Sci. 37, 325-332.

Fricker M, Neher JJ, Zhao JW, Théry C, Tolkovsky AM, Brown GC (2012) MFG-E8 Mediates Primary Phagocytosis of Viable Neurons during Neuroinflammation. J Neurosci. 32, 2657-66.

Fricker M, Oliva-Martin MJ, Brown GC (2012) Primary phagocytosis of viable neurons by microglia activated with LPS or Abeta is dependent on calreticulin/LRP phagocytic signalling. Journal of Neuroinflammation, 13, 9.

Neher JJ, Neniskyte U, Zhao ZW, Bal-Price A, Tolkovsky AM & Brown GC (2011) Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol. 186, 4973-83.

Barauskaite J, Grybauskiene R, Morkuniene R, Borutaite V, Brown GC (2011) Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis. Br J Pharmacol. 162:1136-42.

Other websites: www.guybrown.net www.neuroscience.cam.ac.uk/directory/profile.php?gcb3