L13 Flashcards

1
Q

describe microglia

A

they are small cells (smallest glia cell) which are highly branched

each normally own domain (15-30µm)

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2
Q

what % of glial cells do microglia make up

A

5-20%

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3
Q

how are you able to identify microglia

A

whith

Immuno-cytochemical identification

Iba1 - actin binding proteins

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4
Q

what are the functions of microglia

A

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

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5
Q

describe the distribution of microglia

A

Varies dependent on region

Greater in grey matter

Around synapses

With astrocytes

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6
Q

where do microglia stem from

A

development from haemopoietic cells of bone marrow (therefore they have the same generation as other immune cells)

Myeloid origin (not ectodermal)

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7
Q

when do microglia (MG) invade the CNS

A

in late embryonic development

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8
Q

describe the shape of MG

A

they have a variable shape depending on the arrangement of the actin cytoskeleton

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9
Q

what is Iba1 (actin binding protein 1) involved in

A

shape changes of the MG

We used this to identify microglia and it is involved in them dividing

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10
Q

are microglia able to divide

A

yes

Renew slowly at a median rate of 28% per year, and some
microglia last for more than two decades.

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11
Q

describe the ultrastructure of MG (what they would look like in an electron micrograph)

A

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

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12
Q

the microglia cells form depends on its function

what are the 2 forms that they can have

A

resting and activated

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13
Q

describe the resting state of MG cells

A

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

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14
Q

describe the activated state of MG cells

A

also known as Ameoboid

free movement throughout the neural tissue as it is scavenging,
phagocytose debris,

this is also the state in Development/pruning

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15
Q

what are the 3 reasons we are interested in MG function

A

we are interested in their

resting/servalent state

ability to detect injury

response to injury

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16
Q

why are we interested in MG resting state

A

we are interested in their ability to …

sense the condition of the extracellular milieu

synaptic pruning and developmental apoptosis, neurogenesis

assessing synapses

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17
Q

why are we interested in MG ability to detect injury

A

we want to know more about receptors in the microglial cell membrane and how they initiate the process of active response

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18
Q

why are we interested in MG cells response to injury

A

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

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19
Q

how often is the entire volume of the brain surveyed by microglia cells

A

every 4-5 hours

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20
Q

Microglia actively survey and shape
neuronal circuit structure and function

why is this important

A

for homeostasis of the synapses

surveillance, pruning, phagocytosis, synaptic plasticity

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21
Q

what are some examples of neurological disorders that MG are associated with

A

OCD and retts syndrome

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22
Q

what is Apoptosis

A

Apoptosis is the process of programmed cell death

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23
Q

what 2 things have effects on synaptic and neural development

A

cytokines/inflammation factors and growth factors

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24
Q

what is the effect of cytokines/inflammation factors on synaptic development

A

synaptic pruning

25
Q

what is the effect of cytokines/inflammation factors on neural development

A

apoptosis

26
Q

what is the effect of growth factors on synaptic development

A

synaptic plasticity

27
Q

what is the effect of growth factors on neural development

A

neurogenesis (formation of new neurons)

28
Q

what happens when a single protein in microglia is disrupted

A

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

29
Q

how do the microglia affect neurotransmission and synaptic plasticity

A

It affects basal neurotransmission and synaptic plasticity by releasing soluble factors

They also act on astrocytes

30
Q

what is fraktaline signaling

A

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)

31
Q

how do microglia know what syannapes to phagocytose

A

via fractalkine signaling

32
Q

what are the implications in neurogenesis for healthy MG

A

phagocytosis of apoptotic and dysfunctional progenitors

support progenitor migration

synaptic mantaniace

secretion of trophic factors

fine tuned fractalkine signaling pathway

33
Q

what are the consequences on neurogenesis from pathologically activated MG

A

impeared phagocytosis of apoptotic and dysfunctional progenitors

dysfunctional progenitor migration

failure of synaptic mantaniace

secretion of cytotoxic factors

deregulated fractalkine signaling pathway

34
Q

Microglia actively survey the environment with pattern recognition receptors (PRRs).

what do these receptors detect

A

That recognise molecular patterens of pathogens

35
Q

what do toll like receptors recognise

A

bacterial lipids and viral DNA

36
Q

describe the toll like receptors (TLR) and what each side does

A

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
37
Q

what is the overall response to TLR activation

A

Tailors immune response to the specific pathogen

causing inflammation / defense

38
Q

why do microglia also have receptors for neurotransmitters

A

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

39
Q

what happens when MG become overactivated

A

they produce cytotoxic factors which are (in high doses) neurotoxic

40
Q

when MG are overactivated they produce cytotoxic factors which are neurotoxic

what are some examples of these

A

Superoxide, nitric oxide, tumour necrosis factor-α

41
Q

Causes of MG overactivation are not well understood

what could be some reasons as to why this happens (2 reasons)

A

in response to environmental toxins - pesticide

many neurodegenerative disease cause overactivation of many microglia
- eg Alzheimer’s disease, microglial activation increases as disease progresses

42
Q

when do MG produce reactive oxygen species

A

when toll like receptors are activated

43
Q

why would MG make reactive oxygen species

A

because it is important for cell signaling

44
Q

what happens when reactive oxygen species get too high

A

microglial apoptotic cell death or – too much proinflammatory gene expression causing neurotoxicity

NOTE: overactivity ROS acts extracellularly

45
Q

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

A

Lipopolysaccahride (E coli),

paraquat (chemical herbicide),

MPTP (synthetic heroin -> acute Parkinsonian symptoms),

amyloid beta, thrombin etc.

46
Q

in what diseases is NADPH oxidase activation to produce ROS

A

Alzheimer’s disease

Parkinson’s disease

Involved in the neural damage in response to cerebral vascular
dysfunction

47
Q

how do MG cause astrocytic dysfunction

A

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

48
Q

Air pollution is an environmental factor that causes activation of MG

what does this cause

A

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)

49
Q

how could targeting MG be a potential treatment of AD

A

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)

50
Q

what causes the overactivation of MG in AD

A

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

51
Q

why do we want to understand gene expression on MG

A

Gene expression can show how MG switch states in disease

If we can understand the gene expression then we can target the diseased microglia

52
Q

where are ependymal cells found

A

They line the fluid filled cavities of the brain

They are within the ventricle and the choroid plexus villi forms the CSF

53
Q

what do ependymal cells form

A

a barrier between the brain and the CSF

54
Q

describe the structure of ependymal cells

A

Cuboidal - columnar shape with apical microvilli, cilia

they also contain intermediate filaments

55
Q

what are some functions of ependymal cells (5 roles)

A

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)?

56
Q

how do ependymal cells control CSF flow

A

They do it by recovery stroke

57
Q

what is brain washing

A

We have brain washing when the brain washes itself with new CSF

This helps clear the brain of the toxic waste

58
Q

how often does brainwashing occur

A

The brain is rinsed every 20 min

59
Q

how do ependymal cells provide Trophic and metabolic support

A

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