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Year 4 - Neuroscience and Mental Health BSc > Microglia > Flashcards

Microglia Flashcards

1
Q

What are microglia?

A
  • Resident immune cells of the brain
  • CNS macrophages
  • Constantly survey their environment and respond to changes in homeostasis
  • Involved in all neurological diseases (infarct, MS, FTD, ALS.ect)
  • Mediators between our environment (age, sleep, diet and microbiome) and our brains (via immune cells causing inflammation)
  • May be responsible for obesity associated cognitive decline (cope et al) and neuro-inflammation in offspring of pregnant women (Kang et al)
  • Lots of expansions, migratory and phagocytic activity
  • Covered in receptors to sense the environment
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2
Q

List cells of the CNS

A
  • Neurons
  • Astrocytes
  • Oligodendrocytes
  • Microglia (CNS macrophage)
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3
Q

What are macrophages?

A
  • Innate immune cells
  • Recognise danger (non-self and damaged self)
  • Phagocytose pathogens
  • Attract other cells
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4
Q

Describe distribution and structure of microglia

A
  • Throughout the CNS
  • 5-10% of brain cells
  • Higher density in certain regions (eg. midbrain)
  • Highly ramified morphology (very branched)
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5
Q

Compare microglia and macrophages

A
  • Different gene transcriptions (Healy et al)
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6
Q

Describe how we study microglia

A

Cells in a dish (eg. human, rodent, cell lines, iPS derived)

  • Pros: easy, cheap and can manipulate the cells
  • Cons: in vivo signalling lost

Animal studies (EAE, APP, 6-OHDA)

  • Pros: can sacrifice animal and look at tissue
  • Cons: Wrong animal and wrong disease (EAE is not the same as MS), difference in gene expression

Brain banks

  • Pros: Correct animal, correct disease
  • Cons: One time point (no intervention)

In living people (experimental medicine/ clinical trials) - histology and live cells from human tissue

  • Pros: correct animal, correct disease and correct stage of disease. Can intervene
  • Cons: Limited in what we can measure, expensive
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7
Q

Describe iPS cell studies

A
  • Induced pluripotent stem cell derived microglia
  • May use a fibroblast (from control or a patient with a disease)
  • Caveat: if you take an adult cell to an embrioid state the cell loses various environmental factors which may have influenced the disease
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8
Q

Describe 3D cell cultures

A

‘organ on a chip’

  • Take cells and allow formation of embrioid bodies and then don’t let them attach to the bottom of the dish using a spinning reactor
  • This allows cell to cell actions to imitate the body more than occurs in 2D structure
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9
Q

List other myeloid innate immune cells for CNS

A

Parenchyma
- Microglia

CNS interfaces

  • Perivascular macrophages
  • Choroid plexus macrophage
  • Meningeal macrophage
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10
Q

Describe interaction between microglia and the PNS

A
  • Via the blood brain barrier
  • Peripheral blood cells and soluble molecules can have direct effects on the brain and microglia (eg. study where young mouse blood given to old mouse blood ‘aging, neurodegeneration and brain rejuvenation’)
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11
Q

List other immune competent cells in the brain

A
  • Astrocytes
  • Pericytes (surround endothelial cells, part of the vascular wall)

Neurons and oligodendrocytes

  • Production of immune molecules (cytokines, growth factors)
  • Express antigen presentation molecules
  • Phagocytose/ ingest extracellular material
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12
Q

Describe the origin of microglia

A
  • Yolk sac of the embryo (myeloid recursors)
  • Migrate via blood vessels
  • First wave of 3
  • Enter CNS at E9 before closure of BBB
  • Co-develop with NPCs
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13
Q

Compare M0, M1 and M2 macrophages

A
  • M0 are resting (in healthy brains)
  • M1 are pro-inflammatory (can be induced in the dish by inducing bacterial cell wall. Altered morphology, secrete cytokines and altered gene expression). Become phagocytic.
  • M2 are reparative (studied in the lab with IL4/IL14)
  • However, this model is in vitro, and does not happen in vivo. The number of cell types is many more than this
  • Become phagocytic after activation
  • Hyper-ramified in long term disease
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14
Q

Describe functions of microglia

A

Normal macrophage function

  • Surveillance
  • Mount immune response
  • Attract other immune cells
  • Phagocytose pathogen
  • Present antigen
  • Injury resolution
  • Phagocytosis of apoptotic cells and debris
  • Tissue repair
  • Transform into an active state if necessary

CNS specific function

  • Dynamic interaction with synapses and other brain cells
  • Synaptic pruning
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15
Q

How do microglia perform surveillance?

A
  • Spread out in a grid-like pattern

- Long thin processes monitor the environment (constantly extending and retracting)

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16
Q

Describe neuron-microglial interactions

A
  • Neuronal membrane protein CD200 binds receptor on microglia to dampen microglial activity.
  • Neuronal production of CX3CL1 (fraktalkine) binds receptor on microglia to reduce activation.
  • Monitor synaptic activity
17
Q

GIve examples of immune function of microglia in disease

A
  • Spinal injury, form neuroprotective scar (proliferation). Recruit astrocytes by IGF-1 to form glial scar, and promote neuron and oligodendrocyte survival
  • Migration in amyloid plaques
  • Phagocytose dying/foreign cells
  • Antigen processing, with end feet on the endothelial cells. They recruit T cells and break down the BBB to present HLA class II molecules. (APCs) Hotspots for this are the choroid plexus and glymphatics
18
Q

Give an example of CNS specific functions of microglia

A

Synaptic pruning

  • Prenatally, neurons have far more synapses than in the mature brain
  • They are pruned by microglia – mediated by complement-mediated phagocytosis
  • This process continues post-natally (physiologically)
  • May contribute to pathology in later life
  • Has been studied in the optic nerve, allowing the brain to distinguish information from each eye
19
Q

Describe the roles of microglia in disease

A

Aging

  • Microglial ‘degeneration’
  • Loss of ‘flexible’ phenotype
  • Over-activation – increased pro-inflammatory cytokine secretion
  • Reduced phagocytosis
  • “Age-associated immune senescence”
  • Glia-degenerative disease - occurring before neuronal damage

Alzheimers

  • Genetic risk-factor evidence is strong for AD. Early onset - amyloid related genes (APP etc). Late onset - genes expressed by microglia, a role in immune function
  • Microglia accumulate around amyloid plaques, with insufficient phagocytosis. Thought to be a dysregulation of beneficial microglia functions
  • CD33 dampens microglia activity and prevents phagocytosis of amyloid
  • Gain of detrimental function (mimics damage associated molecular patterns, produce ROS and activate inflammasome)

GWAS studies for other diseases are less clear
- Many Parkinson’s risk genes highly expressed in microglia, but also in other cells: LRRK2, GBA.

Common hypothesis (not sure how true it is):

  • Microglia protective early in the disease. Limit damage, protect neurons.
  • Later, they become overwhelmed and start contributing to damage

Year 4 - Neuroscience and Mental Health BSc (23 decks)

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