Microglia Flashcards
Describe the origin of microglia and other CNS myeloid cells Understand the roles of microglia in health Understand the contribution of microglia to disease
What are macrophages?
Innate immune cells that recognise danger from non-self or damaged self, phagocytose pathogens, attract other immune cells, and clear up damage
Name 3 ways microglia and neurons are in contact
Physical contact, contact through soluble mediators released by healthy neurons, and contact through neurotransmitters
Name a soluble mediator released by neurons and detected by macrophages
CX3CL1, detected by CXC3R1
State an advantage and disadvantage of using cells in vitro to study microglia
Adv: easy, can manipulate cells
Dis: In vivo signalling has been lost, so may not be representative
State an advantage and disadvantage of using animal models to study microglia in disease
Adv: Can sacrifice the animal and look at tissue
Dis: Wrong animal, and wrong disease as models are used
What disease is modeled by the 6-OHDA rodent model?
Parkinson’s disease
State an advantage and disadvantage of using brain banks to study microglia in disease
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
What proportion of brain cells is made up by macrophages?
5-10%
Name 3 types of macrophages found at CNS interfaces
Perivascular macrophages, choroid plexus macrophages, and meningeal macrophages
Are macrophages more abundant in the white or grey matter?
White matter
Which progenitor cells do microglia originate from?
Haematopoeitic stem cells
Which cells do macroglia produce?
Oligodendrocytes, astrocytes, and polydendrocytes
How are microglia distinct from other resident myeloid cells?
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
Name three functions of normal macrophages
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)
State a function of microglia not possessed by macrophages
Dynamic interaction with synapses - pruning of synapses from the pre-natal period into adulthood
Name a marker possessed by microglia and not macrophages
P2Y12 (also TMEM119)
What signals to microglia that a particular synapse should be pruned?
Compliment
Why can clopidogrel inhibit synaptic plasticity in rodent models?
It is a P2Y12 blocker that can cross the blood-brain barrier. It inhibits microglia and hence inhibits synaptic pruning
Why do cerebellar microglia express phagocytic markers, when striatal microglia do not?
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
Name 5 functions upregulated in activated microglia
Migration, cell proliferation, antigen presentating capabilities, phagocytosis, and innate immune cell surface receptors
Why do activated microglia secrete both pro-inflammatory and anti-inflammatory compounds?
Pro-inflammatory compounds as part of the immune response, and anti-inflammatory compounds to avoid excess damage to surrounding cells
Describe the physical activity of microglia in their resting state in vivo
They are not migratory - their cell bodies remain fixed - but their processes are highly motile, covering their entire suveillance area in an hour
What activates microglia after axon transection?
ATP release from neurons
Why do microglia displace axosomatic terminals in transected axons?
So that the microglial and neuronal membranes become opposed. Deafferentation protects axotomised neurons from afferent excitatory impulses
Why are in vitro experiments on primary microglia not representative of in vivo microglia?
Without the CNS environment, many genes are upregulated or downregulated, changing their protein expression and phenotype
How do activated macrophages in vitro respond to being exposed to lipopolysaccharide?
They change to a highly pro-inflammatory phenotype, express CD80, develop amoeboid morphology, and change their gene expression
How do activated macrophages in vitro respond to being exposed to IL4/IL13?
They change to a reparative phenotype, express CD209, and release the IL10 cytokine
Describe the common hypothesis of microglia in CNS disease
Microglua are protective early on in disease, but later on become overwhelmed and start contributing to damage
Describe two ways in which microglial function has been found to be abnormal in models of Alzheimer’s disease
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
Describe evidence of the common hypothesis of microglia in ALS
Induced microglial proliferation at the pre-symptomatic stage delays disease presentation, however induced microglial proliferation at a symptomatic stage worsens disease
Describe two pieces of evidence for microglial involvement in Parkinson’s disease
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
