Author : Amy Megan Smith
Publisher :
ISBN 13 :
Total Pages : 217 pages
Book Rating : 4.:/5 (852 download)
Book Synopsis Adult Human Microglia by : Amy Megan Smith
Download or read book Adult Human Microglia written by Amy Megan Smith and published by . This book was released on 2013 with total page 217 pages. Available in PDF, EPUB and Kindle. Book excerpt: The immune system continuously monitors and protects the central nervous system (CNS) throughout health and disease. Microglia are the resident immune cells of the CNS. Present throughout the brain parenchyma and in constant communication with the peripheral immune system, microglia are essential regulators of brain physiology. The adult human brain is prone to immune dysregulation in neurodegeneration and normal ageing. Understanding the roles and mechanisms of microglia in the adult human brain will aid the understanding of normal and degenerative brain processes. Despite increasing evidence of species differences, the majority of microglial studies are performed using rodent cells and few studies have addressed the questions of microglial function and regulation in the context of the adult human brain. This thesis explores the phenotypic diversity of microglia from adult human brain tissue - the primary microglia which are themselves part of neurological diseases. This study makes use of the unique resources of the Neurological Foundation of New Zealand Human Brain Bank and the Centre for Brain Research Biobank. Microglia were isolated from biopsy and post-mortem human adult brain tissue and grown in mixed glial cultures with astrocytes and brain derived fibroblast-like cells. The transcription factor PU.1 is important for myeloid cell development and function, but has not previously been investigated in adult human microglia. In this study PU.1 has been identified for the first time in adult human brain tissue and microglia, and demonstrated to be critical for microglial survival and phagocytosis. Short interfering RNA (siRNA) proved to be a highly effective and useful tool for investigating primary human microglial function. Microglial phenotype is highly dynamic and changes according to their external environment. Macrophage Colony-Stimulating Factor (M-CSF) promoted a distinct microglial phenotype with increased PU.1 expression, and induced microglia to proliferate and undergo phagocytosis. Conversely, interferon-y (IFNy) induced an activated microglial phenotype with increased Human Leukocyte Antigen (HLA) expression and secretion of pro-inflammatory cytokines and chemokines. Despite Transforming Growth Factor-♭1 being reported to inhibit IFNy-induced HLA expression in rodent microglia, this response was completely absent in human microglia. Instead this mechanism was active in brain derived fibroblast-like cells. As regulators of the brain microenvironment, microglia affect many physiological processes including proliferation and fate determination of neural progenitor cells (NPCs). Microglia in the constitutively neurogenic regions of the adult human brain were found to have greater proliferative potential than microglia from cortical non-neurogenic regions. Interestingly, neurogenic region microglia showed enhanced responses to M-CSF. NPCs were also isolated from the neurogenic regions of adult human brain tissue and the immune cytokine IFNy was found to direct differentiation of NPCs towards an astrocytic fate. Immune cells and molecules are essential for CNS function and the study of adult human microglia provides a unique insight into the workings of these vital cells. Targeting microglia to limit detrimental neuroinflammation, for example using siRNA directed against PU.1 or by using M-CSF molecule mimics, is a potential therapy for future treatment of neurological diseases.