Module A: Receptors and Disease Flashcards
Why are astrocytes an important drug target?
(3 key reasons)
- Astrocytes have a critical role in supporting the long-term viability of neurons. Preventing the loss of astrocytes and other glia is a good way to reduce neuronal cell death.
- Excessive astrocyte proliferation is the cause of glioblastoma, a major brain tumour. Controlling astrocyte proliferation can reduce the risk of developing glioblastoma.
- During an inflammatory/immune response, astrocytes release inflammatory factors (such as cytokines) that can damage neurons. Anti-inflammatory treatment strategies can reduce harm caused by inflammation. This is especially important, as most diseases of the brain result in an inflammatory response.
How are astrocytes commonly detected (i.e. as part of immunohistology)
- By using nuclear stains that are selective for astrocytes.
- Expression GFAP is a strong selective marker, but not all astrocytes express the protein.
- Therefore, GFAP staining is often used in conjunction with other less selective stains such as CCR4, in order to identify astrocytes.
What does GFAP stand for? What is it, and what does it do?
- GFAP = “Glial Fibrillary Acidic Protein”
- It is a protein expressed by astrocytes (and a few other cells) that is implicated in maintaining cytoskeletal structure.
What are the key functions of astrocytes?
- Vital support for neurons (maintenance of homeostasis)
- The clearance of excess neurotransmitters from synaptic clefts (ie. glutamate) to prevent excitotoxicity
- Maintenance of the blood brain barrier
- “First line of immune defence” as part of the brain’s innate immune system
How do astrocytes contribute to the brain’s immune response?
- Release of and response to cytokines/chemokines as part of the inflammatory and immune response
- Attraction of other immune cells to the site of injury (via chemotaxis)
- Production of neurotrophic factors to reduce neuronal attrition (such as BDNF - Brain-Derived Neurotrophic Factor)
Name four cytokines produced by astrocytes.
MCP-1, IP10, IL-8, MIP
During periods of ischaemia to areas of the brain (such as in a cerebral infarction/stroke) reduced oxygen supply and nutrients results in rapid death of neurons.
Astrocytes have a much better survival rate. Why is this thought to be?
During periods of ischaemia, astrocytes produce transcription factors called Hypoxia-Inducible Factors (HIFs), which likely orchestrate downstream adaptation to ischaemia in astrocytes.
Give an example of strong evidence supporting the role of astrocytes as “guardians and supporters” of neurons.
Co-cultural studies where both neurons and astrocytes are placed into culture reveal that neurons are dependent upon astrocytes for survival.
When astrocytes are removed from the culture, the long-term viability of the neurons decreases sharply.
What is the name of the neuroglial cells colloquially referred to as “brain macrophages”?
Microglia.
List the key features of microglia.
- They are immune cells of monocytic or myeloid origin.
- They come in several different functional subsets, each with its own immunomarkers and morphology.
- As part of the adaptive immune system, they produce cytokines and also function as antigen-presenting cells.
- Microglia serve a critical role during repair of the brain by phagocytosing dead cells and cell debris: a “machine for clearing dead neurons.” (Not all microglia are phagocytic, however).
Where, specifically, would one find the subtype of microglia called “perivascular macrophages?”
What does this indicate about the function of these cells?
Near blood vessels in the brain, between the parenchyma and the perivascular space.
They likely serve a key role in “screening” compounds that cross the blood-brain barrier.
Perivascular microglia also release factors that stimulate the proliferation of endothelial cells, promoting repair and regeneration of blood vessels in the brain.
