Neuroinflammation Flashcards
What are the main types of glia in the brain?
▪️Oligodendrocytes
▪️Astrocytes
▪️Microglia
▪️Ependymal/epithelial cells
What are pericytes?
Cells along the walls of capillaries that play a key role in maintaining the BBB and the regulation of immune cell entry into the CNS
Where do microglia come from?
Myeloid progenitors in the blood island of the yolk sac
What cell type is produced during the first wave of primitive haemopoiesis?
Microglia
What cell type is produced during the second wave of primitive haemopoiesis?
Blood cells
What cell type shows similar actovity to monocyte and are almost indistinguishable in the brain?
Microglia
What are the resident inflammatory cells of the CNS and how much of the glia population do they constitute?
Microglia (~10-20%)
How do you identify microglia in the brain?
They express unique marker proteins such as Iba-1 and C3 complement receptor
Where do oligodendrocytes come from?
From oligodendrocyte progenitor cells (OPCs) in the neuroectoderm
During gestation, which glia are produced early on and which come later?
Early = microglia
Later = astrocytes and oligodendrocytes
What is the main role of oligodendrocytes?
To form the myelin sheath around axons in the CNS, required for efficient signal conductance.
They also provide metabolic support to neurons.
How do you identify oligodendrocytes in the brain?
Unique myelin-based protein markers such as NG2, Olig1, MBP, PLP, and MOG
What type of cell makes up around 50% of the glia population?
Astrocytes
Where do astrocytes originate from?
The neuroectoderm
What determines what kind of cell a glia becomes and what it’s function will be?
Gene expression
What are the main roles of astrocytes?
▪️Regulate synaptic connectivity
▪️Maintenance of ionic/neurotransmitter homeostasis in extracellular space
▪️Formation of gap junctions and syncytial networks
▪️Wound healing and limitation of inflammation
What type of cell is particularly important in guiding circuit formation in development?
Astrocytes
What are the unique markers of astrocytes?
GFAP, vimentin, GLAST
How can microglia be further classified into subsets?
▪️Characterise cells by single cell RNA sequencing
▪️Then group them based on similarities and differences
How many clusters of microglia have been identified in the human brain?
9
How does microglia vary across brain regions?
More or less the same but not identical - individual genes may have different prominence
Cell __________ depends on location and reflects ____________.
▪️Morphology
▪️Function
What might be the function of an astrocyte sitting very close to a synapse?
To remove and recycle excess neurotransmitters which may be toxic, like glutamate.
Maintaining ionic/neurotransmitter homeostasis in extracellular space.
What might be the function of an astrocyte lined up along an endothelial cell?
Supporting the maintenance of the BBB
What happens to microglia when they become activated?
They retract their processes in and become more phagocytic to encapsulate what they have detected
What happens to microglia when they are homeostatic (resting)?
They are surveillant and ramified, growing and projecting processes to detect signals
What happens to microglia as we age?
Their morphology changes and they become senescent - no longer as phagocytic as they should be
What happens to microglia in older age, particularly in neurodegeneration?
They become dystrophic
What are the two main categories of microglia function?
▪️Tissue maintenance and homeostasis
▪️Protection
What do microglia protect against?
Trauma (even the slightest pathological insult) and pathogens
What are the four maintenence and homeostatic roles of microglia?
▪️Clearing apoptotic cells
▪️Neuron protection
▪️Synaptic pruning and circuit creation
▪️Tissue maintenance
What are the two types of signals microglia respond to?
PAMPS and DAMPS
What is DAMPS?
Damage Associated Molecular Patterns
What is PAMPS?
Pathogen Associated Molecular Patterns
What damage signals might microglia respond to?
▪️ ATP, ADP, and phosphatidyl serine from stressed or dying cells
▪️ Protein aggregates such as amyloid
▪️ Lipid signals indicating myelin damage
How do microglia receive signals?
Via Pattern Recognition Receptors (PRR)
respond to “eat me” signals
How might microglia react to “eat me” signals?
▪️ Phagocytosis
▪️ Chemotaxis (movement in response to signal, may signal for others to assist)
▪️ Cytokines and chemokines (tags microglia can respond to)
▪️ Complement and coagulation factors
What is the microglia doing when remified?
Resting - reaching our to sample environment, highly metabolic
What happens when microglia is activated?
Becomes an activated amoeboid - changes gene expression pattern, secretions, behaviours etc
Sets of complex chain of events
What do microglia processes do when extended?
▪️ Contact other cells
▪️ Contact each other (e.g., to surround amyloid)
▪️ Engulf extracellular material
How do microglia proliferate and/or move towards signals?
Chemotaxis
What is M1 microglia behaviour?
Pro-inflammatory
▪️ “classically” activated - pathogen related
▪️ More likely to produce toxic substances (e.g., oxidative free radicals, hydrogen peroxide)
▪️ Secretion of cytokines/chemokines (e.g., IL-1B, IL-6, TNF-alpha)
▪️ Defence against pathogens and tumour cells
▪️ Triggers damage to healthy neurons
Chronically activated in AD?
What is M2 microglia behaviour?
Anti-inflammatory
▪️ “alternatively” activated - damage response
▪️ Tissue remodelling/repair
▪️ Angiogenesis
▪️ Doesn’t produce toxins
How can M1 be toxic to self?
Inflammasome activation:
▪️ Increased production of reactive oxygen species = bystander damage when chronically activated causing continuous cycle
What is HAM?
Human Alzheimer’s Microglia (human post mortem brain)
What is DAM?
Damage Associated Microglia (amyloid mouse models)
What might cause chronic stimulation of the immune system/microglia?
Either pathogen or “sterile” pathogen mimic
Immune system stays on as signal does not go away
What conditions may be associated with increased immune activation in the brain?
▪️ Dementia
▪️ Depression
▪️ Schizophrenia/psychosis
What conditions may be associated with increased immune activation in the periphery?
▪️ Obesity/metabolic disturbance
▪️ Ageing
▪️ Infection
▪️ Autoimmune disease (e.g., arthritis)
____________ immune activation can prime ___________
▪️ Systemic
▪️ Microglia
What are the two pathway for peripheral signal transfer to the brain?
▪️ Neural pathway - molecules in blood may stimulate vagus nerve (e.g., cytokine signals, macrophages)
▪️ Humoral pathway - cells cross BBB and start producing cytokines or the signals themselves cross the BBB (may also pass via ventricles)
Why might astrocytes be involved in HD, epilepsy, and ALS?
Relation to glutamate/glutamine removal?
What is sterile inflammation?
Microglia respond to signals from things that are not pathogens such as protein aggregates in neurodegeneration and dysfunctional dying neurons
IS IT PROTECTING OR DAMAGING?
What is the evidence for the contribution of neuroinflammation to AD?
▪️ Activated microglia clustered round amyloid correlates with symptoms
▪️ Immune-associated risk genes overrepresented
▪️ Rare variants in immune/microglial genes
▪️ Protection with NSAIDs?
What happens to microglia in the presence of proteinopathy in AD?
▪️ Surround them
▪️ Become amoeboid
▪️ Increase in number
▪️ Correlate with disease markers (neuronal death and behavioural symptoms)
(less so for NFTs)
What is TREM2?
▪️ Gene highly expressed in macrophages including microglia
▪️ Receptor dysfunction = impaired phagocytosis
▪️ Potential new target for AD treatment and intervention
What is TSPO?
A marker for microglia activation seen with PET
Shows greater activation in AD
Why might TNF-alpha produced by microglia contribute to AD?
Pro-inflammation toxicity
▪️ Higher synaptic excitatory/inhibitory ratio
▪️ Increased glutamate, AMPA and NMDA
▪️ Decreased GABA-A
▪️ Increased ROS and excitatory damage
Glutamate system = synaptic transmission, plasticity, learning, and memory
What is the evidence for pro-inflammation toxicity in AD?
Deficiencies seen in many stages of the glutamate cycle
