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Scientific Foundations > Neuroinflammation > Flashcards

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
Q

What happens to microglia when they become activated?

A

They retract their processes in and become more phagocytic to encapsulate what they have detected

26
Q

What happens to microglia when they are homeostatic (resting)?

A

They are surveillant and ramified, growing and projecting processes to detect signals

27
Q

What happens to microglia as we age?

A

Their morphology changes and they become senescent - no longer as phagocytic as they should be

28
Q

What happens to microglia in older age, particularly in neurodegeneration?

A

They become dystrophic

29
Q

What are the two main categories of microglia function?

A

▪️Tissue maintenance and homeostasis
▪️Protection

30
Q

What do microglia protect against?

A

Trauma (even the slightest pathological insult) and pathogens

31
Q

What are the four maintenence and homeostatic roles of microglia?

A

▪️Clearing apoptotic cells
▪️Neuron protection
▪️Synaptic pruning and circuit creation
▪️Tissue maintenance

32
Q

What are the two types of signals microglia respond to?

A

PAMPS and DAMPS

33
Q

What is DAMPS?

A

Damage Associated Molecular Patterns

34
Q

What is PAMPS?

A

Pathogen Associated Molecular Patterns

35
Q

What damage signals might microglia respond to?

A

▪️ ATP, ADP, and phosphatidyl serine from stressed or dying cells
▪️ Protein aggregates such as amyloid
▪️ Lipid signals indicating myelin damage

36
Q

How do microglia receive signals?

A

Via Pattern Recognition Receptors (PRR)

respond to “eat me” signals

37
Q

How might microglia react to “eat me” signals?

A

▪️ 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
Q

What is the microglia doing when remified?

A

Resting - reaching our to sample environment, highly metabolic

39
Q

What happens when microglia is activated?

A

Becomes an activated amoeboid - changes gene expression pattern, secretions, behaviours etc

Sets of complex chain of events

40
Q

What do microglia processes do when extended?

A

▪️ Contact other cells
▪️ Contact each other (e.g., to surround amyloid)
▪️ Engulf extracellular material

41
Q

How do microglia proliferate and/or move towards signals?

A

Chemotaxis

42
Q

What is M1 microglia behaviour?

A

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
Q

What is M2 microglia behaviour?

A

Anti-inflammatory
▪️ “alternatively” activated - damage response
▪️ Tissue remodelling/repair
▪️ Angiogenesis
▪️ Doesn’t produce toxins

44
Q

How can M1 be toxic to self?

A

Inflammasome activation:
▪️ Increased production of reactive oxygen species = bystander damage when chronically activated causing continuous cycle

45
Q

What is HAM?

A

Human Alzheimer’s Microglia (human post mortem brain)

46
Q

What is DAM?

A

Damage Associated Microglia (amyloid mouse models)

47
Q

What might cause chronic stimulation of the immune system/microglia?

A

Either pathogen or “sterile” pathogen mimic

Immune system stays on as signal does not go away

48
Q

What conditions may be associated with increased immune activation in the brain?

A

▪️ Dementia
▪️ Depression
▪️ Schizophrenia/psychosis

49
Q

What conditions may be associated with increased immune activation in the periphery?

A

▪️ Obesity/metabolic disturbance
▪️ Ageing
▪️ Infection
▪️ Autoimmune disease (e.g., arthritis)

50
Q

____________ immune activation can prime ___________

A

▪️ Systemic
▪️ Microglia

51
Q

What are the two pathway for peripheral signal transfer to the brain?

A

▪️ 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
Q

Why might astrocytes be involved in HD, epilepsy, and ALS?

A

Relation to glutamate/glutamine removal?

53
Q

What is sterile inflammation?

A

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
Q

What is the evidence for the contribution of neuroinflammation to AD?

A

▪️ Activated microglia clustered round amyloid correlates with symptoms
▪️ Immune-associated risk genes overrepresented
▪️ Rare variants in immune/microglial genes
▪️ Protection with NSAIDs?

55
Q

What happens to microglia in the presence of proteinopathy in AD?

A

▪️ Surround them
▪️ Become amoeboid
▪️ Increase in number
▪️ Correlate with disease markers (neuronal death and behavioural symptoms)

(less so for NFTs)

56
Q

What is TREM2?

A

▪️ Gene highly expressed in macrophages including microglia
▪️ Receptor dysfunction = impaired phagocytosis
▪️ Potential new target for AD treatment and intervention

57
Q

What is TSPO?

A

A marker for microglia activation seen with PET

Shows greater activation in AD

58
Q

Why might TNF-alpha produced by microglia contribute to AD?

A

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
Q

What is the evidence for pro-inflammation toxicity in AD?

A

Deficiencies seen in many stages of the glutamate cycle

Scientific Foundations (27 decks)

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