Microglia

Question 1

What are macrophages?

Answer 1

Innate immune cells that recognise danger from non-self or damaged self, phagocytose pathogens, attract other immune cells, and clear up damage

Question 2

Name 3 ways microglia and neurons are in contact

Answer 2

Physical contact, contact through soluble mediators released by healthy neurons, and contact through neurotransmitters

Question 3

Name a soluble mediator released by neurons and detected by macrophages

Answer 3

CX3CL1, detected by CXC3R1

Question 4

State an advantage and disadvantage of using cells in vitro to study microglia

Answer 4

Adv: easy, can manipulate cells
Dis: In vivo signalling has been lost, so may not be representative

Question 5

State an advantage and disadvantage of using animal models to study microglia in disease

Answer 5

Adv: Can sacrifice the animal and look at tissue
Dis: Wrong animal, and wrong disease as models are used

Question 6

What disease is modeled by the 6-OHDA rodent model?

Answer 6

Parkinson’s disease

Question 7

State an advantage and disadvantage of using brain banks to study microglia in disease

Answer 7

Adv: Correct animal, correct disease
Dis: snapshot of a single time point, usually at the end of the disease, some tissue degradation, cannot test interventions

Question 8

What proportion of brain cells is made up by macrophages?

Answer 8

5-10%

Question 9

Name 3 types of macrophages found at CNS interfaces

Answer 9

Perivascular macrophages, choroid plexus macrophages, and meningeal macrophages

Question 10

Are macrophages more abundant in the white or grey matter?

Answer 10

White matter

Question 11

Which progenitor cells do microglia originate from?

Answer 11

Haematopoeitic stem cells

Question 12

Which cells do macroglia produce?

Answer 12

Oligodendrocytes, astrocytes, and polydendrocytes

Question 13

How are microglia distinct from other resident myeloid cells?

Answer 13

They develop from extra-embryonic yolk cells in utero instead of the bone marrow. This makes them mesodermal cells, and means they must self-renew

Question 14

Name three functions of normal macrophages

Answer 14

Surveillance of the environment, mounting an immune response (attracting immune cells, phagocytosis, and antigen presentation), and injury resolution (phagocytosis of apoptotic cells and debris, and tissue repair)

Question 15

State a function of microglia not possessed by macrophages

Answer 15

Dynamic interaction with synapses - pruning of synapses from the pre-natal period into adulthood

Question 16

Name a marker possessed by microglia and not macrophages

Answer 16

P2Y12 (also TMEM119)

Question 17

What signals to microglia that a particular synapse should be pruned?

Answer 17

Compliment

Question 18

Why can clopidogrel inhibit synaptic plasticity in rodent models?

Answer 18

It is a P2Y12 blocker that can cross the blood-brain barrier. It inhibits microglia and hence inhibits synaptic pruning

Question 19

Why do cerebellar microglia express phagocytic markers, when striatal microglia do not?

Answer 19

The cerebellum is an area of high neuronal turnover, requiring phagocytosis of apoptotic neurons by microglia. In contrast, the striatum is an area of low neuronal turnover, so phagocytosis is not required

Question 20

Name 5 functions upregulated in activated microglia

Answer 20

Migration, cell proliferation, antigen presentating capabilities, phagocytosis, and innate immune cell surface receptors

Question 21

Why do activated microglia secrete both pro-inflammatory and anti-inflammatory compounds?

Answer 21

Pro-inflammatory compounds as part of the immune response, and anti-inflammatory compounds to avoid excess damage to surrounding cells

Question 22

Describe the physical activity of microglia in their resting state in vivo

Answer 22

They are not migratory - their cell bodies remain fixed - but their processes are highly motile, covering their entire suveillance area in an hour

Question 23

What activates microglia after axon transection?

Answer 23

ATP release from neurons

Question 24

Why do microglia displace axosomatic terminals in transected axons?

Answer 24

So that the microglial and neuronal membranes become opposed. Deafferentation protects axotomised neurons from afferent excitatory impulses

Question 25

Why are in vitro experiments on primary microglia not representative of in vivo microglia?

Answer 25

Without the CNS environment, many genes are upregulated or downregulated, changing their protein expression and phenotype

Question 26

How do activated macrophages in vitro respond to being exposed to lipopolysaccharide?

Answer 26

They change to a highly pro-inflammatory phenotype, express CD80, develop amoeboid morphology, and change their gene expression

Question 27

How do activated macrophages in vitro respond to being exposed to IL4/IL13?

Answer 27

They change to a reparative phenotype, express CD209, and release the IL10 cytokine

Question 28

Describe the common hypothesis of microglia in CNS disease

Answer 28

Microglua are protective early on in disease, but later on become overwhelmed and start contributing to damage

Question 29

Describe two ways in which microglial function has been found to be abnormal in models of Alzheimer’s disease

Answer 29

1) Amyloid deposition triggers the tagging of synapses with C1q, a marker for microglial pruning
2) Overexpression of microglial CD33, which interacts with neuronal sialic acid to inhibit phagocytosis, prevents phagocytosis of dead tissue

Question 30

Describe evidence of the common hypothesis of microglia in ALS

Answer 30

Induced microglial proliferation at the pre-symptomatic stage delays disease presentation, however induced microglial proliferation at a symptomatic stage worsens disease

Question 31

Describe two pieces of evidence for microglial involvement in Parkinson’s disease

Answer 31

1) Microglial density is increased in post-mortem brains of Parksinon’s disease patients
2) In rodent cultures, microglia mediate alpha-synuclein toxicity in a process dependent on NADPH oxidase