Glia III

University of Southampton - BIOL2059: Microglia and Other Brain Immune Cells

Page 1:

  • University of Southampton BIOL2059: Microglia and other brain immune cells.

Page 2: Recap: Macrophage Subpopulations in the Brain

  • Macrophage Subpopulations:

    • Microglial Cells: Resident immune cells of the brain.

    • Meningeal Macrophages: Located in the meningeal layers surrounding the brain.

    • Choroid Plexus Macrophages: Found within the choroid plexus, involved in cerebrospinal fluid production and immune response.

    • Perivascular Macrophages: Located in the perivascular space, participate in blood-brain barrier maintenance and immune surveillance.

  • Reference: Nature Reviews | Neuroscience, Prinz & Priller, 2014.

Page 3: Brain Development

  • Key Developmental Stages:

    • E9.5: Neuroepithelium colonization.

    • E13.5: Introduction of newborn astrocytes and pericytes in brain development.

  • Sources of Macrophages in Brain Development:

    • Yolk Sac Macrophage: Early source of monocytes during fetal development.

    • Fetal Liver Monocytes: Contribute to macrophage populations.

    • Hematopoiesis in the Fetal Liver: Process through which blood cells are formed and magnetic inheritance occurs.

  • Adult Brain States:

    • Steady-State Brain: Homeostasis with a stable microglial population.

    • Inflamed Brain: Increased activity of bone marrow-derived macrophages, questioning the identity of microglia in inflammation.

Page 4: Microglial Function and Types

  • Surveillant Microglia: Constantly monitor the brain environment for changes.

  • Microglial Classification:

    • Pruning Microglia: Involved in synapse elimination.

    • Systemic Sensing Microglia: Respond to systemic inflammation.

    • Neuromodulatory Microglia: Involved in modulation between pre-synaptic and post-synaptic interactions.

  • Cellular Interactions:

    • Self-Renewal: Microglia maintain their population through self-renewal processes.

    • Phagocytic Microglia: Engulf apoptotic cells and debris.

  • Sources: Gomez-Nicola & Perry, The Neuroscientist, 2014.

Page 5: Microglial Surveillance

  • Distance Covered by Microglial Processes:

    • 10.0 micrometers (μm) range surveillance in the brain to assess the local environment.

  • Reference: Davalos et al., 2005.

Page 6: Microglial Diversity

  • Diversity Characteristics:

    • Morphological Diversity: Variation in microglia shapes reflecting their functional states.

Page 7: Quantifying Microglial Population Changes

  • Study Types: Comparison between various genetic backgrounds (e.g., Young WT, Aged WT, Young CCR2-/-).

  • Quantitative Data:

    • Numbers from multiple brain regions such as: Frontal lobe (gray matter and white matter), Motor cortex, Occipital lobe, and more.

  • Percentage of Microglial Cells by Region: Quantitative analysis showing diversity.

  • References: Askew et al 2017; Mittelbronn et al., 2001.

Page 8: Continuing Microglial Diversity Studies

  • Proliferation Rates:

    • Comparisons between young and aged microglia in different brain regions (e.g., CA1-2, DG).

    • Rates (%) detailed using distinct samples.

  • Diversity Factors: Morphological diversity, regional density, and turnover rates among microglia.

  • References: Askew et al 2017.

Page 9: Microglial Transcriptional and Functional Diversity in Mice

  • Exploration of Diversity:

    • References: Hickman et al., Nat Neurosci, 2013; Butovsky et al., Nat Neurosci, 2014; Grabert et al., Nat Neurosci, 2016.

Page 10: Microglial Transcriptional and Functional Diversity in Humans

  • Core Transcriptional Module: Evident similarities to mouse microglia, highlighting evolutionary conservation of function.

  • Environment-Dependent Transcriptional Module: Includes gene hits related to Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Multiple Sclerosis (MS).

  • Reference: Gosselin et al., 2017.

Page 11: Synaptic Pruning and Apoptotic Cell Clearance by Microglia

  • Essential Role of Microglia: Facilitating synaptic pruning and clearing of apoptotic cells during development.

  • Illustration of Processes: Microglia extend processes to engulf synapses and apoptotic cells.

  • References: Sharper et al., Neuron, 2012; Sierra et al., Cell Stem Cell, 2010.

Page 12: Experimental Paradigm of Synaptic Pruning

  • Retinal Ganglion Cells (RGCs): Form synaptic connections within the dorsal lateral geniculate nucleus (dLGN).

  • RGC Input Dynamics: During the maturation phase, RGCs from the same and different eyes compete for synaptic territory.

Page 13: Quantitative Experimental Findings on Microglia during Pruning

  • Microglial/Involved Markers:

    • CTB-594 (Contra), CTB-647 (Ipsi), GFP (microglia), CD68 (lysosome).

  • Results of Study: Percentages relating to microglial volume and CTB engulfment measures.

  • References: Schafer et al., Neuron, 2012.

Page 14: Synaptic Pruning and Complement Dependency

  • Functional Insights: Differences in engulfment behavior between Wild Type (WT) and CR3 Knockout (KO) microglia during synaptic pruning.

  • Results Indicated: Variability in engulfment percentages normalized to WT.

  • References: Schafer et al., Neuron, 2012.

Page 15: Microglial Impact on Forebrain Development

  • Microglial Activity Influence: Effects of perturbed microglial activity on dopaminergic axon outgrowth and positioning of neocortical interneurons.

  • Reference: Squarzoni et al., 2014.

Page 16: Apoptotic Cell Clearance from Development to Adulthood

  • Developmental Lifecycle of Microglia:

    • Critical Periods of Survival: Main (1-4 days), Secondary (1-3 weeks).

    • Stages of Newborn Cell Clearance: Quiescent, Amplifying, Early Neuroblasts to Granule Cell Layer.

  • Reference: Sierra et al., Cell Stem Cell, 2010.

Page 17: Apoptotic Cell Clearance Mechanism Overview

  • Phagocytosis of Apoptotic Newborn Cells: Engaging microglia in the early stages to maintain neurogenesis in the hippocampus.

Page 18: Immune Roles of Microglia

  • Role in Immune Response:

    • PAMPs (Pathogen-associated molecular patterns): Example - Lipopolysaccharides (LPS).

    • DAMPs (Damage-associated molecular patterns): Example - ATP.

  • Pro-inflammatory Cytokines Released by Microglia:

    • Examples: IL-1ß, IL-6, TNF-α, CCL2, ROS, and NO.

  • Anti-inflammatory Response: Mediated through cytokines such as IL-10 and the actions of M2 microglia.

Page 19: Microglial Activation States in Neurodegeneration

  • Different Activation States of Microglia:

    • 'Resting' Microglia: Exhibit lower activity in healthy brain status.

    • 'Switched' Microglia: Become activated with chronic neurodegenerative states including acute and chronic inflammation.

  • References: Perry et al., 2010.

Page 20: Microglia States and Nomenclature Evolution

  • Shift in Microglial Conceptualization:

    • Old View: Rigid, dichotomic categorization (e.g., M1 vs M2, resting vs activated).

    • New View: Acknowledgement of multiple states and complexity in function.

  • Characters of New Perspectives:

    • Proteomic, metabolomic, transcriptomic, and epigenetic considerations.

Page 21: Understanding Complexity in Microglial Behavior

  • Determinants Affecting Microglial Function:

    • Contextual factors including species, age, ontogeny, sex, and spatial location, and environmental influences on microglial activity.

    • Layers of Complexity: Including interactions in morphology, motility, and metabolic functions reflected through specialized studies.

Page 22: Mandatory Reading and References on Microglial Role in Alzheimer’s Disease

  • Epidemiological Evidence: Linking innate immunity to the causation of Alzheimer’s Disease through various studies and GWAS findings.

  • References: Holmes et al., 2009; Karch & Goate, 2014;Jun et al., 2010; Guerreiro et al., 2013; Jonsson et al., 2013.

Page 23: Temporal Evolution of Microglial Profile in Alzheimer’s Disease

  • Focus on TREM2’s Role:

    • Investigating the functional significance of TREM2 and whether microglial subpopulations exhibit distinct roles during AD progression.

  • Reference: Keren-Shaul et al., Cell, 2017.

Page 24: Microglial Functional Diversity in Alzheimer’s Disease

  • Key Functional Dynamics: Analysis of the functional diversity of microglia linked to neurodegenerative processes, focusing on transcriptional regulation mechanisms associated with TREM2.

  • References: Various microglial genes are implicated in AD progression and neuroprotection processes within experimental models.

Page 25: Microglial Responses Across Different Neurodegenerative Conditions

  • Microglial Activation Across Conditions: Difference in responses across ALS, AD, and Healthy Brain states reflected by a surveillance versus an activated state.

  • Roles of Perivascular and Meningeal Macrophages: Their contributions to overall brain immune responses and potential regenerative roles.

  • References: Gomez-Nicola & Perry, The Neuroscientist, 2014.

Page 26: Microglial Mechanisms in Amyloid Pathology Neuromodulation

  • Pathological Dysregulations: Exploring the roles of receptor interactions in regulating microglial function concerning amyloid beta and related AD phenomena.

  • Impact on Synaptic Dysfunction and Tau Spread: Microglial disruption linked to progressive cognitive decline in Alzheimer’s Disease.

  • Reference: Simon et al 2018.

Page 27: Summary of Key Findings

  1. Phenotypic Complexity of Microglial Populations: Display substantial regional and age-dependent diversity.

  2. Microglia's Developmental Roles: Critical in brain development, especially in circuit refinement.

  3. Healthy Brain Functionality of Microglia: They maintain their surveillant profile, integral to synaptic modulation.

  4. Reversible Activation Role: Upon disruption of brain homeostasis through environmental challenges, microglia can change function dramatically.

  5. Microglia’s Central Role in Chronic Neurodegenerative Diseases: Key to understanding the progression of disorders like Alzheimer’s Disease and others chronic neuroinflammatory responses.