Neuroinflammation Flashcards

1
Q

What are the main types of glia in the brain?

A

▪️Oligodendrocytes
▪️Astrocytes
▪️Microglia
▪️Ependymal/epithelial cells

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2
Q

What are pericytes?

A

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

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3
Q

Where do microglia come from?

A

Myeloid progenitors in the blood island of the yolk sac

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4
Q

What cell type is produced during the first wave of primitive haemopoiesis?

A

Microglia

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5
Q

What cell type is produced during the second wave of primitive haemopoiesis?

A

Blood cells

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6
Q

What cell type shows similar actovity to monocyte and are almost indistinguishable in the brain?

A

Microglia

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7
Q

What are the resident inflammatory cells of the CNS and how much of the glia population do they constitute?

A

Microglia (~10-20%)

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8
Q

How do you identify microglia in the brain?

A

They express unique marker proteins such as Iba-1 and C3 complement receptor

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9
Q

Where do oligodendrocytes come from?

A

From oligodendrocyte progenitor cells (OPCs) in the neuroectoderm

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10
Q

During gestation, which glia are produced early on and which come later?

A

Early = microglia
Later = astrocytes and oligodendrocytes

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11
Q

What is the main role of oligodendrocytes?

A

To form the myelin sheath around axons in the CNS, required for efficient signal conductance.

They also provide metabolic support to neurons.

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12
Q

How do you identify oligodendrocytes in the brain?

A

Unique myelin-based protein markers such as NG2, Olig1, MBP, PLP, and MOG

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13
Q

What type of cell makes up around 50% of the glia population?

A

Astrocytes

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14
Q

Where do astrocytes originate from?

A

The neuroectoderm

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15
Q

What determines what kind of cell a glia becomes and what it’s function will be?

A

Gene expression

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16
Q

What are the main roles of astrocytes?

A

▪️Regulate synaptic connectivity
▪️Maintenance of ionic/neurotransmitter homeostasis in extracellular space
▪️Formation of gap junctions and syncytial networks
▪️Wound healing and limitation of inflammation

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17
Q

What type of cell is particularly important in guiding circuit formation in development?

A

Astrocytes

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18
Q

What are the unique markers of astrocytes?

A

GFAP, vimentin, GLAST

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19
Q

How can microglia be further classified into subsets?

A

▪️Characterise cells by single cell RNA sequencing
▪️Then group them based on similarities and differences

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20
Q

How many clusters of microglia have been identified in the human brain?

A

9

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21
Q

How does microglia vary across brain regions?

A

More or less the same but not identical - individual genes may have different prominence

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22
Q

Cell __________ depends on location and reflects ____________.

A

▪️Morphology
▪️Function

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23
Q

What might be the function of an astrocyte sitting very close to a synapse?

A

To remove and recycle excess neurotransmitters which may be toxic, like glutamate.

Maintaining ionic/neurotransmitter homeostasis in extracellular space.

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24
Q

What might be the function of an astrocyte lined up along an endothelial cell?

A

Supporting the maintenance of the BBB

25
What happens to microglia when they become activated?
They retract their processes in and become more phagocytic to encapsulate what they have detected
26
What happens to microglia when they are homeostatic (resting)?
They are surveillant and ramified, growing and projecting processes to detect signals
27
What happens to microglia as we age?
Their morphology changes and they become senescent - no longer as phagocytic as they should be
28
What happens to microglia in older age, particularly in neurodegeneration?
They become dystrophic
29
What are the two main categories of microglia function?
▪️Tissue maintenance and homeostasis ▪️Protection
30
What do microglia protect against?
Trauma (even the slightest pathological insult) and pathogens
31
What are the four maintenence and homeostatic roles of microglia?
▪️Clearing apoptotic cells ▪️Neuron protection ▪️Synaptic pruning and circuit creation ▪️Tissue maintenance
32
What are the two types of signals microglia respond to?
PAMPS and DAMPS
33
What is DAMPS?
Damage Associated Molecular Patterns
34
What is PAMPS?
Pathogen Associated Molecular Patterns
35
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
36
How do microglia receive signals?
Via Pattern Recognition Receptors (PRR) respond to "eat me" signals
37
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
38
What is the microglia doing when remified?
Resting - reaching our to sample environment, highly metabolic
39
What happens when microglia is activated?
Becomes an activated amoeboid - changes gene expression pattern, secretions, behaviours etc Sets of complex chain of events
40
What do microglia processes do when extended?
▪️ Contact other cells ▪️ Contact each other (e.g., to surround amyloid) ▪️ Engulf extracellular material
41
How do microglia proliferate and/or move towards signals?
Chemotaxis
42
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?
43
What is M2 microglia behaviour?
Anti-inflammatory ▪️ "alternatively" activated - damage response ▪️ Tissue remodelling/repair ▪️ Angiogenesis ▪️ Doesn't produce toxins
44
How can M1 be toxic to self?
Inflammasome activation: ▪️ Increased production of reactive oxygen species = bystander damage when chronically activated causing continuous cycle
45
What is HAM?
Human Alzheimer's Microglia (human post mortem brain)
46
What is DAM?
Damage Associated Microglia (amyloid mouse models)
47
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
48
What conditions may be associated with increased immune activation in the brain?
▪️ Dementia ▪️ Depression ▪️ Schizophrenia/psychosis
49
What conditions may be associated with increased immune activation in the periphery?
▪️ Obesity/metabolic disturbance ▪️ Ageing ▪️ Infection ▪️ Autoimmune disease (e.g., arthritis)
50
____________ immune activation can prime ___________
▪️ Systemic ▪️ Microglia
51
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)
52
Why might astrocytes be involved in HD, epilepsy, and ALS?
Relation to glutamate/glutamine removal?
53
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?
54
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?
55
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)
56
What is TREM2?
▪️ Gene highly expressed in macrophages including microglia ▪️ Receptor dysfunction = impaired phagocytosis ▪️ Potential new target for AD treatment and intervention
57
What is TSPO?
A marker for microglia activation seen with PET Shows greater activation in AD
58
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
59
What is the evidence for pro-inflammation toxicity in AD?
Deficiencies seen in many stages of the glutamate cycle