L13 Flashcards
describe microglia
they are small cells (smallest glia cell) which are highly branched
each normally own domain (15-30µm)
what % of glial cells do microglia make up
5-20%
how are you able to identify microglia
whith
Immuno-cytochemical identification
Iba1 - actin binding proteins
what are the functions of microglia
homeostasis – routinely monitor extracellular environment
activity dependent synapse elimination
phagocytosis of surplus neural precursor cells
defence function -> normal (-> exacerbate inflammation)
many roles in disease processes
describe the distribution of microglia
Varies dependent on region
Greater in grey matter
Around synapses
With astrocytes
where do microglia stem from
development from haemopoietic cells of bone marrow (therefore they have the same generation as other immune cells)
Myeloid origin (not ectodermal)
when do microglia (MG) invade the CNS
in late embryonic development
describe the shape of MG
they have a variable shape depending on the arrangement of the actin cytoskeleton
what is Iba1 (actin binding protein 1) involved in
shape changes of the MG
We used this to identify microglia and it is involved in them dividing
are microglia able to divide
yes
Renew slowly at a median rate of 28% per year, and some
microglia last for more than two decades.
describe the ultrastructure of MG (what they would look like in an electron micrograph)
elongated nuclei “bean” shaped
with peripheral heterochromatin
scattered cisternae of rough endoplasmic reticulum and Golgi
complexes at both poles
a microglial cell is adjacent to a neuron there is usually a thin astrocytic process
the microglia cells form depends on its function
what are the 2 forms that they can have
resting and activated
describe the resting state of MG cells
Resting (not moving)
but Ramified (branched) processes survey the
microenvironment (Surveying microglia),
Maintain a constant level of available microglia to
rapidly detect and fight infection
describe the activated state of MG cells
also known as Ameoboid
free movement throughout the neural tissue as it is scavenging,
phagocytose debris,
this is also the state in Development/pruning
what are the 3 reasons we are interested in MG function
we are interested in their
resting/servalent state
ability to detect injury
response to injury
why are we interested in MG resting state
we are interested in their ability to …
sense the condition of the extracellular milieu
synaptic pruning and developmental apoptosis, neurogenesis
assessing synapses
why are we interested in MG ability to detect injury
we want to know more about receptors in the microglial cell membrane and how they initiate the process of active response
why are we interested in MG cells response to injury
we are interested in the….
synthesis and release of chemokines – attract other microglia
Proliferation or entry of monocytes via BBB (often faulty in disease)
Become motile, apoptosis, phagocytic
how often is the entire volume of the brain surveyed by microglia cells
every 4-5 hours
Microglia actively survey and shape
neuronal circuit structure and function
why is this important
for homeostasis of the synapses
surveillance, pruning, phagocytosis, synaptic plasticity
what are some examples of neurological disorders that MG are associated with
OCD and retts syndrome
what is Apoptosis
Apoptosis is the process of programmed cell death
what 2 things have effects on synaptic and neural development
cytokines/inflammation factors and growth factors
what is the effect of cytokines/inflammation factors on synaptic development
synaptic pruning
what is the effect of cytokines/inflammation factors on neural development
apoptosis
what is the effect of growth factors on synaptic development
synaptic plasticity
what is the effect of growth factors on neural development
neurogenesis (formation of new neurons)
what happens when a single protein in microglia is disrupted
If there is a mutation then it can reach out to grap the protein but it wont be able to pull it in and engulf it
how do the microglia affect neurotransmission and synaptic plasticity
It affects basal neurotransmission and synaptic plasticity by releasing soluble factors
They also act on astrocytes
what is fraktaline signaling
Fractalkine signaling happens via soluble fractalkine that is released by the neurons and the glia have the fractaline receptors for it
This is how the neuron and the microglia talk to each other
This modulates the microglial synappes interactions to effect LTP (long term potentiation)
how do microglia know what syannapes to phagocytose
via fractalkine signaling
what are the implications in neurogenesis for healthy MG
phagocytosis of apoptotic and dysfunctional progenitors
support progenitor migration
synaptic mantaniace
secretion of trophic factors
fine tuned fractalkine signaling pathway
what are the consequences on neurogenesis from pathologically activated MG
impeared phagocytosis of apoptotic and dysfunctional progenitors
dysfunctional progenitor migration
failure of synaptic mantaniace
secretion of cytotoxic factors
deregulated fractalkine signaling pathway
Microglia actively survey the environment with pattern recognition receptors (PRRs).
what do these receptors detect
That recognise molecular patterens of pathogens
what do toll like receptors recognise
bacterial lipids and viral DNA
describe the toll like receptors (TLR) and what each side does
Extracellular side of TLR-recognition of
the microbial product
Cytoplasmic side of TLR - TIR domain
- recruit signalling molecules
- alter kinase activation / transcription factors
- > Modify gene expression
what is the overall response to TLR activation
Tailors immune response to the specific pathogen
causing inflammation / defense
why do microglia also have receptors for neurotransmitters
They also have receptors for neurotransmitters eg NMDA and AMPA sol they can limit the inflammatory environment so it doesn’t interfere with the synapps
what happens when MG become overactivated
they produce cytotoxic factors which are (in high doses) neurotoxic
when MG are overactivated they produce cytotoxic factors which are neurotoxic
what are some examples of these
Superoxide, nitric oxide, tumour necrosis factor-α
Causes of MG overactivation are not well understood
what could be some reasons as to why this happens (2 reasons)
in response to environmental toxins - pesticide
many neurodegenerative disease cause overactivation of many microglia
- eg Alzheimer’s disease, microglial activation increases as disease progresses
when do MG produce reactive oxygen species
when toll like receptors are activated
why would MG make reactive oxygen species
because it is important for cell signaling
what happens when reactive oxygen species get too high
microglial apoptotic cell death or – too much proinflammatory gene expression causing neurotoxicity
NOTE: overactivity ROS acts extracellularly
Toxins can cause neurotoxicity through activation of the NADPH oxidase ->
which leads to increased ROS (reactive oxygen species)
what are some examples of these toxins
Lipopolysaccahride (E coli),
paraquat (chemical herbicide),
MPTP (synthetic heroin -> acute Parkinsonian symptoms),
amyloid beta, thrombin etc.
in what diseases is NADPH oxidase activation to produce ROS
Alzheimer’s disease
Parkinson’s disease
Involved in the neural damage in response to cerebral vascular
dysfunction
how do MG cause astrocytic dysfunction
The ROS inhibits the glutamate transporters in the astrocytes therefore it is not being mopped up.
This causes problems to the neurons as extra glutamate will bind to extracellular/extrasynaptic receptors increasing Ca influx at the synappes leading to excitotoxicity neuron cell death
Air pollution is an environmental factor that causes activation of MG
what does this cause
prenatal air pollution exposure - increased risk of neurodevelopmental disorders – eg autism spectrum disorder (ASD).
increased inflammatory cytokine protein
altered the morphology of microglia, = activation or a delay in maturation,
only male mice
- this was because there was increased overlap between MG and neurons when offspring was prenatally exposed to DEP
NOTE: Diesel exhaust particles (DEP)
how could targeting MG be a potential treatment of AD
TAU attracts the immune cells
APOE collects inside MG transforming them into their activated form causing them to attack the neurons as well
If you can limit the microglia when they are in there activated form (late in the disease process) can stop then from killing the neurons (stop it from getting worse)
what causes the overactivation of MG in AD
They found that there was a inituall stage change in gene expression and then there is a decrease in the immune checkpoints causing them to become more of a phagocytosis factor
why do we want to understand gene expression on MG
Gene expression can show how MG switch states in disease
If we can understand the gene expression then we can target the diseased microglia
where are ependymal cells found
They line the fluid filled cavities of the brain
They are within the ventricle and the choroid plexus villi forms the CSF
what do ependymal cells form
a barrier between the brain and the CSF
describe the structure of ependymal cells
Cuboidal - columnar shape with apical microvilli, cilia
they also contain intermediate filaments
what are some functions of ependymal cells (5 roles)
Brain-CSF barrier and filter
Inflammatory response
A regulator of osmotic pressure
Control the concentrations of
regulatory peptides
control CSF flow
Trophic and metabolic support
In specialized locations secrete cerebrospinal fluid
Function as neural stem cells, (self-renewal and multipotency)?
how do ependymal cells control CSF flow
They do it by recovery stroke
what is brain washing
We have brain washing when the brain washes itself with new CSF
This helps clear the brain of the toxic waste
how often does brainwashing occur
The brain is rinsed every 20 min
how do ependymal cells provide Trophic and metabolic support
There are several growth factors in the ependymal cells and there are particular regions in the brain where they can make CSF as well but majority of their role is for movement
