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neuroanatomy 2021 > Lecture 13: Microglia and Ependymal Cells > Flashcards

Lecture 13: Microglia and Ependymal Cells Flashcards

1
Q

microglia can be a

A

friend and a foe

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2
Q

ependymal cells are important …

A

important defence mechanism in looking after our internal environment

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3
Q

Microglia features

A

small cells, highly branched,
each normally own domain (15-30μm)
constitute between 5-20% of all glial cell
important for surveying and reacting to the internal environment

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4
Q

Identifying microglia

A

Difficult to identify
Immuno-cytochemical identification
Iba1 - actin binding proteins therefore good for marking microglia

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5
Q

Functions of microglia

A

homeostasis – routinely monitor extracellular environment
activity dependent synapse elimination - can manage synapses and if they need to be removed they can do that
phagocytosis of surplus neural precursor cells
defence function -> normal (-> exacerbate inflammation) (can go wrong and this can cause disease)
many roles in disease processes

Have different functions depending on the stage of life, region of the CNS and the environment (whether it is health or disease) ultimately they act by sensing and regulating the environment of the CNS, they eliminate certain structures such as pathogens, dead cells and protein aggregates and others and can secrete cytokines and neurotrophic factors for this purpose and for other immune functions too, during life they can contribute to neurogenesis, neuronal circuit shaping, vascular shaping, and homeostasis

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6
Q

Distribution of microglia

A

varies dependent on region
greater in grey matter
around synapses
with astrocytes

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7
Q

Microglial morphology - embryonic development

A

Invade CNS in late embryonic development
́development from haemopoietic cells of bone marrow
́Myeloid origin (not ectodermal) ́

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8
Q

Microglial morphology - in adult

A

In adult
́Variable shape – rearrangements of actin cytoskeleton ́Iba1– shape changes (protein that contributes to the shape change)
́Can divide - can divide quite a lot but they can also slowly renew themselves, can be around for a long time (2 decades) but also can replicate in response to an immune or toxin attack as well
́Renew slowly at a median rate of 28% per year, and some microglia last for more than two decades.

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9
Q

Microglial morphology

A

Invade CNS in late embryonic development
́development from haemopoietic cells of bone marrow
́Myeloid origin (not ectodermal) ́

In adult
́Variable shape – rearrangements of actin cytoskeleton ́Iba1– shape changes
́Can divide
́Renew slowly at a median rate of 28% per year, and some microglia last for more than two decades.

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10
Q

Microglial origin

A

Not derived from the same embryonic lines as neurons and astrocytes, they actually share the same origin as macrophages and other haemopoetic cells so really they originate from those cells that are scavenging CNS for plaque, damaged neurons and infectious agents as well

develop from haemopoetic cells of bone marrow - myeloid origin rather than ectodermal

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11
Q

Ultrastructure of microglia

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 (arrow)

Has dark cytoplasm and it has granules of rER and Golgi complexes at both poles so its nuclei takes on a bean like shape

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12
Q

Two states of microglia (remember form depends on the function)

A

resting state and activated state

from resting go through morphological changes to become activated, structure becomes quite different

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13
Q

Resting state of microglia overall function

A

(not moving)
but
Ramified (branched) processes survey the microenvironment (Surveying microglia) - can survey all the time to see if they need to react to something that is in the brain
Maintain a constant level of available microglia to rapidly detect and fight infection - guardians of the brain

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14
Q

IBA1

A

actin binding protein, used to identify microglia

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15
Q

Activated state of microglia overall function

A 
Activated
Ameoboid
free movement throughout the neural tissue =scavenging,
phagocytose debris,
Development/pruning
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16
Q

why are we interested in microglial function?

A

Resting = Surveillant
́sensing the condition of the extracellular milieu
́synaptic pruning (prune if required) and developmental apoptosis, neurogenesis (influences neurogenesis)
assessing synapses

́Detect injury
́Receptors in the microglial cell membrane
́initiate the process of active response

Response to injury
́synthesis and release of chemokines – attract other microglia (can make chemokine etc so it can elicit a response)
Proliferation or entry of monocytes via BBB (often faulty in disease)
Become motile, apoptosis, phagocytic

activity is wide and varied in response to toxicity

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17
Q

resting = surveillant …

A

Resting = Surveillant
́sensing the condition of the extracellular milieu
́synaptic pruning (prune if required) and developmental apoptosis, neurogenesis (influences neurogenesis)
assessing synapses

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18
Q

Microglia - detect injury

A

́Detect injury
́Receptors in the microglial cell membrane
́initiate the process of active response

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19
Q

Microglia - response to injury

A

Response to injury
́synthesis and release of chemokines – attract other microglia (can make chemokine etc so it can elicit a response)
Proliferation or entry of monocytes via BBB (often faulty in disease)
Become motile, apoptosis, phagocytic

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20
Q

By the resting (surveillant) microglia the entire volume of the brain is examined every

A

4 to 5 hours

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21
Q

Four main themes of function for microglia …

A

1 - neural development - really important in programmed cell death
2 - homeostasis of synapses/synaptic interactions - can also survey, monitor and prune presynaptic terminals and dendritic spines to maintain homeostasis of the synapses, phagocytosis, synaptic plasticity
3 - adult neurogenesis - includes phagocytosis adult newborn cells
4 - neurological and psychiatric disorders - associated with these disorders if the physiological functions have been affected in these microglia

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22
Q

Microglia actively

A

survey and shape neuronal circuit structure and function

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23
Q

Microglia and neural development

A

Cytokines/inflammation ….
inflammatory molecules
cytokines
apoptosis can release inflammatory molecules cytokines so that they can assist in synaptic pruning and apoptosis

Growth factors …
Growth factors
promote synaptic plasticity and neurogenesis
the same microglia have the capacity to release growth factors which likely promote synaptic plasticity

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24
Q

Microglia and homeostasis of synapses

A

microglia affect basal neurotransmission and synaptic plasticity i.e. long term potentiation

  • Microglia - sense defunct synapses and phagocytose them in normal brain
  • Via fractalkine
  • Synaptic pruning by microglia is essential for the remodeling of synaptic circuits synaptic plasticity

In the adult brain we have these very soluble factors such as BDNF and TNFalpha that can be released by microglia which affects the basal transmission and plasticity and they can also act directly on astrocytes and affect it as well
In addition, have fractalkine signalling via the soluble fractalkine which are released by neurons and microglia have fractalkine receptors which can modulate the microglia and synapse interactions which can affect LTP behaviour in the mature CNS, the neurons can talk to the microglia and the microglia can also talk to the neurons and affect synaptic plasticity and basal neurotransmission

Microglia are important for basal level functioning in the brain

25
Q

Microglia and neurogenesis

A

microglia regulation of neurogenesis during lifespan

Two regions of the brain where we make new neurons as adults and one is the subventricukqr zone near the lateral ventricle and the other is the subgranular zone which is in the denture gyrus of the hippocampus

Neuro genesis doesn’t replace all the neurons in the brain, only a few that become new neurons, figuring out how to up regrulate theses in neurodegenerative disorders

Important regulation of neuro genesis over age as well, When your have the first* neuronal stem cells hey can phagocytise not very good cells (spoptotic and dysfunctional progenitors), can support progenitor migration, synaptic maintenance, secretion of tropic factors

Over time, disease processes such as Parkinson’s or Alzheimer’s and other modulators factors come into play such as signalling factors, Eli genetic factors, genetic factors and environmental factors

Pathologically activated microglia, has a huge effect on neurogenesis

Can do the opposite of healthy - can impair phagocytosis of apoptosis and dysfunctional progenitors, dysfunctional progenitors migration or altered, failure of synaptic maintenance, secretion of cytotoxic factors

26
Q

The good and the bad of microglia

A

injury to the brain ….

Proliferation and hypertrophy -> GOOD or BAD

27
Q

Good response by microglia to local injury - how does it start?

A

microglia branches quickly hone in on the injury site and then the microglia surround it and form a barrier to protect it, first response to injury that is quire fast so that healing can start

28
Q

Good response by microglia to local injury - PRRs and TLRs

A

Microglia actively survey the environment with pattern recognition receptors (PRRs) - recognise pathogen associated patterns , molecular patterns of pathogens

TLR: Toll-like receptors
= type I transmembrane receptors with extracellular domain

Extracellular side of TLR-recognition of the microbial product
The extracellular side of the TLR recognises the microbial product which sends a message to the cytoplasmic side of the toll like receptor so there it can recruit signal,ing molecules and alter kinase activation/transcription factors and finally it can modify gene expression and can tailor the immune response to the pathogen of origin (reacts to what the pathogen is) therefore it is important for inflammation/defence

Cytoplasmic side of TLR - TIR domain

  • recruit signalling molecules
  • alter kinase activation / transcription factors
  • > Modify gene expression

Tailors immune response to the specific pathogen

Inflammation / defense

29
Q

PRRs =

A

pattern recognition receptors

30
Q

TLRs =

A

toll-like receptors

31
Q

TLR2 and TLR4

A

bacterial lipids

32
Q

TLR3

A

viral DNA

33
Q

TLR9

A

Bacterial DNA

34
Q

ROS

A

reactive oxygen species = neurotoxic

35
Q

Microglial activation is good but can become over activated …

A

Ligand recognized – internalized – eliminated (good)
BUT

́Microglial can become overactivated (BAD)
́produce cytotoxic factors = neurotoxic
́Superoxide, nitric oxide, tumour necrosis factor-α (some are good and actually protect the environment but it about the over activation and overproduction of these factors that makes them bad)

́Causes of overactivation -not well understood
́Environmental toxins - pesticide (environmental toxins such as pesticides can actually activate our microglia)
́Neurodegenerative disease -> many microglia (many are over activated)
́Alzheimer’s disease – microglial activation increases as disease progresses

36
Q

Microglia actively survey the environment with pattern recognition receptors (PRRs) - TLR activated - inflammation/defense over exaggerated/overactivated….

A

Inflammation/defense (over exaggeration causes the problem) = too much ROS (microglial apoptotic cell death or - too much pro inflammatory gene expression

  • > overactivity ROS extracellular
  • > neurotoxicity

ROS can actually be good for signalling but it is the over activation that causes the problems

37
Q

ROS leads to

A

neurodegeneration

38
Q

Toxins can cause neurotoxicity through activation of ___________ -> increased _______

A

NADPH oxidase

ROS (reactive oxygen species)

39
Q

Toxins examples can cause neurotoxicity through activation of NADPH oxidase -> increased ROS

A

Lipopolysaccahride (E coli), paraquat (chemical herbicide), MPTP (synthetic heroin -> acute Parkinsonian symptoms), amyloid beta, thrombin etc.

40
Q

NADPH oxidase activation to produce ROS is activated in….

A

NADPH oxidase activation to produce ROS is activated in; Alzheimer’s disease
Parkinson’s disease
Involved in the neural damage in response to cerebral vascular
dysfunction
(experimentally - Ischaemic stroke is reduced in mice lacking functional NADPH oxidase)

41
Q

becoming activated microglia with ROS

A

activated microglia when they start becoming activated, if there is inflammation we can have kinase activation, transcription factor activation and intracellular ROS concentration increases

need to limit the level of response in the microglia because if there are too many microglia they can get damaged from the ROS as well

42
Q

Microglia can act on other cells … astrocytes…

A

Microglia -> astrocyte dysfunction -> damage

activation of microglia
release cytokines etc

alter astrocyte behaviour 
impaired glutamate uptake 
activation of postsynaptic inotropic glut receptors 
Ca2+ influx 
Excitotoxicity - neuron death

Environment is important at cellular level
Remember in disease - many things are happening at once

Astrocytes are important in mopping up glutamate (another neurotransmitter at synapse), what can happen with microglia is that the production of the ROS in the microglia these can inhibit the glutamate transporters that are in the astrocytes so you have glutamate that is not being mopped up by astrocytes and they are in the extracellular environment in the synapse which will cause a lot of problems with the neurons because it going the bind to extracellular and extrasynaltic receptors which potentially causes increase in calcium concentration in the neurons causing neurotoxicity and killing them - misbehaving microglia can directly affect astrocytes which can then directly affect neurons because of the extra amount of glutamate around and causing that extra toxicity to be around the neurons and therefore you are not going to get the prime depolarisation either

43
Q

Environmental activation of microglia - air pollution

A

Air pollution - pervasive and harmful environmental toxicants modern world,

44
Q

Environmental activation of microglia - ASD

A

Air pollution - pervasive and harmful environmental toxicants modern world,
́ Large scale epidemiological studies - prenatal air pollution exposure - increased risk of neurodevelopmental disorders – autism spectrum disorder (ASD). - link between environmental toxins, microglia and potentially ASD as well

45
Q

Environmental activation of microglia - diesel exhaust particles (DEP)

A

́ Diesel exhaust particles (DEP) = primary toxic component of air pollution -> activate microglia in vitro and in vivo in adult rodents

Impact of gestational exposure to DEP on microglial morphology - developing brains, male and female mice.
́ increased inflammatory cytokine protein
́ altered the morphology of microglia, = activation or a delay in maturation, only male mice

46
Q

Microglia and neurons overlap in juvenile offspring prenatally exposed to DEP

A

increased overlap between microglia and neurons in juvenile offspring prenatally exposed to DEP
overlap affects how the neuron works

volume of microglia is bigger with exposure to DEP particles compared to normal

Male overlap between microglia and neuron is bigger in the exposed vs in the not exposed so they could say that the exposure of the environmental toxin prenatal could affect male mice

does affect mice developmentally

47
Q

Microglial can become over activated and cause neurotoxicity

A

Have a toxic trigger and then release neuro toxic factors and have this direct neuro toxic insult and the neuron responds and you may get this microglia activated from this neuron and then you get a self-perpetuating neurotoxicity cycle happen with these neurons

48
Q

PET images - AD vs normal patient

A

more microglial activation in AD

49
Q

Targeting microglia could be a potential therapy for AD

A

Since we know it is toxic

Tangles of tau protein form inside neurons as Alzheimer’s disease develops. The tangles attract immune cells known as microglia. The protein APOE collects inside microglia, helping the immune cells transform into their activated form. Activated microglia attach and injure neurons, causing brain damage and leading to cognitive decline

If you can eliminate the microglia if they are in this activated form then you can potentially inhibit the death of the neurons

50
Q

DAM - disease microglia

A

a unique microglia type associated with restricting development of AD

How they found
Found a disease microglia -initially have an early stage change in the microglia cells by gene expression and then have a decrease in the immune checkpoints (immune response genes are changing) to cause it to increase phagocytosis and can see this change in the microglia as the genes progress

51
Q

DAM - how they were found

A

How they were found…
Wildtype vs AD model
Single cell RNA sequencing of all immune cells - sequenced all the single cells of the immune cells within the mouse models and looked specifically at the microglia
Found a disease microglia -initially have an early stage change in the microglia cells by gene expression and then have a decrease in the immune checkpoints (immune response genes are changing) to cause it to increase phagocytosis and can see this change in the microglia as the genes progress

52
Q

Gene expression profiles of microglia reveal how microglia…

A

…progressively switch states with disease

homeostatic microglia - stage 1 DAM - stage 2 DAM

53
Q

Hypothetical dual role for disease associated microglia (DAM) in the procession of disease

A

if we can understand the gene expression and understand that there is this progression in the changes of microglia through the activated state then we can actually target this microglia

54
Q

microglia can produce …

A

cytokines (both pro-inflammatory and anti- inflammatory cytokines)
Also:
growth factors, chemokines and neurotrophins.

55
Q

Ependymal cells line

A

the fluid filled cavity of the brain which is the ventricular system, line the ventricular system of the CNS

Ependymal cells are within the ventricle and choroid plexus makes the cerebrospinal fluid (protective from impact), ependymal cells are lining the ventricle where you have the choroid plexus as well and they have cilia which can move cilia, form a bit of a barrier between the CSF and the brain exchanges

56
Q

Ependymal cell shape

A

cuboidal -columnar shape
apical microvilli, cila
contain intermediate filaments

57
Q

Function of ependymal cells

A

Ependymal epithelium: interface between brain and CSF
́Brain-CSF barrier and filter - filtration barrier
́Inflammatory response - can release factors and protect the cells that surround them
́A regulator of osmotic pressure
́ Control the concentrations of regulatory peptides - ensure that their are not too many, regulation

control of CSF flow - can move the CSF through the brain by the cilia (effective stroke pushes fluid and then recovery stroke puts it back in the position to do an effective stroke again)

Trophic and metabolic support
́In specialized locations secrete cerebrospinal fluid
́Function as neural stem cells, (self-renewal and multipotency)? - increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain - The demonstration of endogenous stem/progenitor cells in the hippocampus and the subependymal layer (SEL) of the basal ganglia in the adult mammalian brain has raised the exciting possibility that these undifferentiated cells may be able to generate neurons for cell replacement in neuro- degenerative diseases such as HD.

58
Q

‘Brain-washing’

A

The brain nightly rinses itself though csf so a good night sleep is essential for brain health which might help to clear the brain of the toxic waste, rhythmic waves of blood and csf

neuroanatomy 2021 (32 decks)

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