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Neurodegenerative > Glial Cells In Neurogen > Flashcards

Glial Cells In Neurogen Flashcards

1
Q

90% of cells in the brain are Glial cells

A

Do not carry nerve impulses
PNS - schwann cells
CNS - macroglia 85-90% (astrocyte, ependymal cells, Oligodendrocytes) and microglia (10-15%)

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2
Q

Functions of glia

A

Provide physical support
Supply nutrients and oxygen
Insulate for synaptic communication
Destroy and remove cell debris and unwanted molecules

New discoveries and still being investigated
Developmental roles
Synaptic transmission (modulation)
Fundamental in brain disease and degen

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3
Q

Phylogenetically advantage of glial cells

A

Human 80%
Rat/mice 60%
More complex the brain the more glial
Bigger and more complex astrocyte cells in humans than mice

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4
Q

Development of research into glial cells

A

New staining mechanisms
Improvements in microscopes

Neurone research progressed quicker than glial research

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5
Q

Neuro glia in PNS

A

Schwann cells
Surround axons
Responsible for myelination of axons
Repair

Satellite cells
Surround neuron cell bodies in ganglia
Regulate 02, co2, nutrient and NT levels around neurons in ganglia

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6
Q

Neuro glia in CNS

A

Oligodendrocytes
Myelinated axons
Structural framework

Astrocytes
Maintain BBB
structural support
Regulate ion, nutrient, and dissolved gas levels
Scar tissue formation

Microglia
Remove cell debris, waste and pathogens via phagocytosis

Ependymal cells
Line ventricles (brain) and central canal (spinal cord)
Assist in producing, circulating, and monitory CSF

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7
Q

Developmental structures of the brain

A

Primary structures
Procencephalon
Mesencephalon
Rhinbencephalon

Secondary structures
Telencephalon
Diencephalon
Metencephalon
Myelencephalon
Spinal cord

Yolk sac - extra embryonic layer, progenitors for microglia derive from the yolk sac

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8
Q

Time scale of development

A

Before birth
Neurogenesis
Neuronal migration

Flip genesis and synaptogenesis

After birth
Myelination
Synaptic pruning

Endothelial blood brain barrier with 6 weeks of gestation

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9
Q

Radial glia cells

A

Differentiate from neural progenitors
Somata in the ventricular zone and extending prolongations your the pia
Give rise to all cell lineages
Populate the brain and provide scaffolding for neuronal migration (occurs in regions that are laminated)

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10
Q

From o2a astrocytes and Oligodendrocytes

A

O2a- progenitor than can give rise to astrocyte a and Oligodendrocytes
Acquire identity as they migrate and colonise specific regions (defined by factors they encounter)
First astrocytes
Then ng2 (Oligodendrocytes)

Ng2 cells progenitor to Oligodendrocytes

Immature Oligodendrocytes neurones makes connections via synaptogenesis
Mature Oligodendrocytes fully myelinated

Intrinsic determinists - notch1 and prox1 high in precursor cells
Drop in notch 1 will result in maturation and express proteins like MBP

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11
Q

Schwann cells

A

Neural crest cells give rise to schwann cell precursors (and peripheral sensory and autonomic neurons and satellite cells of dorsal root ganglia)
Immature cells differentiate into myelinating and non myelinating depending on early association with large or small diameter axons
Myelinating - large
Non myelinating- small

De-differentiation is important during Wallerian degeneration

Wraps cell body to myelinate

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12
Q

Astrocytes

A

Astrocyte lineage development poorly defined lacking stage specific markers and defined developmental endpoint
Astrocyte functional heterogeneity is starting to emerge suggesting the number and role of subpopulations is yet to be defined

GFAP - needed for complex morphologies seen in mature astrocytes
Maturation mainly postnatal but express different markers (GFAP and S100b) and have different morphology

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13
Q

Microglia are macrophages but only one of the brains immune population

A

Research relatively new so immune cells not yet fully understood

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14
Q

Research for microglia

A

Mouse, take out brain, single cell dissociation, cell staining, mass cytometry (labelling with antibodies) clustering cell count or single cell resolution
Same cells will cluster together

Resident myeloid cells - broad population and diversity with this category

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15
Q

Development and maintenance of brains immune toolkit: microglia and non prenchymal brain macrophages

A

Microglia inside BBB
Meningeal macrophage- adjacent to the brain but physically connected
Chloroid plexus macrophage - CSF
Perivascular macrophage - perivascular space

Not fully understood - still early in research

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16
Q

Basic characteristics of microglia population

A

Ramified morphology, tiling the brain parenchyma in a mosaic like distribution
Biggest differences in morphology between grey (ramified) and white (bipolar) matter
Variable densities in different regions
Equipped with a repertoire of immune sensor and reactants allowing rapid and plastic reactions to distributions of the brains homeostasis

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17
Q

Systemic sensing microglia

A

Survailent microglia
Proliferating microglia
Phagocytosis microglia
Neuromodulatory microglia
Pruning microglia (overshoot, becomes over active in neurodegenerative?)

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18
Q

Nissl staining resulted in discovery of microglia

A

Microglia related to macrophages
Rabies - abundance of microglia so immune function
Entry through one point and then expanding
High MHC classII used for antigen presentation

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19
Q

Colonisation and lineages

A

Erythromyeloid progenitors (RMPs) derived from yolk sac and give rise to all macrophage populations
The brain is colonised directly (without relay in liver) and earlier that other organs

Uncommitted EMPs express specificarkers eg CD32 and cKit
EMPs develop via macrophage ancestor population A1 into the A2 progenitor population that commit to microglia cells
Express different markers

20
Q

Specification of microglia during development

A

In the brain, environmental factors eg CSF1, IL34 and TGFbeta play fundamental roles in shaping, maintaining and reinforcing microglia identity
Intrinsic signals would be the same regardless of the environment
So both intrinsic and extrinsic play a role in maturation

21
Q

Astrocytes roles

A

Neurogenesis and gliogenesis in the adult brain
Neuronal guidance in developmental: role of radial glia
Regulation of synaptogenesis and synaptic maturation
Structural function: microarchitecture of the brain. Astrocytes define and connect domains that include neurones, synapses and blood vessels and communication through gap junctions
Creation of the BBB
synaptic modulation

22
Q

Tripartite synapse

A

~60% of axon dendritic synapses surrounded by astrogial membranes (hippocampus)
80% of large perforated synapses rn wrapped by astrocyte
Cerebellum- interaction of purkinje cells with Bergman cells (astrocyte of cerebellum) each enwrapping 2000-6000 synaptic contacts

23
Q

Tripartite synapse evidence

A

Astrocytes are excitable cells - in response to presynaptic or postsynaptic stimulation, astrocytes are capable of producing transient changes in their intracellular calcium concentrations through release of ca stores from the ER
Astrocytes communicate bidirectionally with neurones - detect NTs and other signals released from neurons at the synapse and can release their own NTs or gliotransmitters that are in turns capable of mortifying their electrophysiological excitability of neurones

24
Q

Blood brain barrier

A

Barrier between Intra cerebral blood vessels and the brain parenchyma
Formed by tight junctions between endothelial cells and astrological end feet
Present throughout the brain except circumventrucular organs (CVOs), neurohypophysis, pineal gland, subfornical organ and laminate terminalis involved in endocrine signalling
Select what molecules can access the brain
Important for removal of molecules too
Sealed compartment
Astrocyte cover capillaries - so have to cross 4 membranes

25
Q

Glial and axonal injury- glial scar

A

Astrocyte try to contain lymph nodes by increasing proliferation near the injury - protective layer to prevent spread
Glial scar will form cavity, whatever in the cavity will be degraded and filled with static fluid. Never goes away

26
Q

Astrocyte subtypes in neurodegenerative

A

Non reactive astrocytes
A1 phenotype- astrocytes producing toxic factors that accelerate degen
Identified molecules that can repair and prevent conversion of these astrocytes eg TGF beta so remain untranslated
TNF or C1q then change to A1 and are neurodegenerative and toxic
Ischemia - deprecation of o2, result in production of a2 which is more neuroprotective

27
Q

Myelinating cells

A

oligodendrocytes: Each myelinate multiple axons in CNS (~10 axons per cell)
Schwann cells: myelinating and non. Wrap single axon

Myelination dependent on axonal diameter. Radial growth of axon and myelin sheath (number of lamellae) are interdependent. G ratio of axons to myelin lamellae 1:10 in both CNS and PNS
Interdependence if glia axons: loss of axons results in degen oligodendrocytes and dedifferentiation if schwann cells and axons degenerate in absence of appropriate support from schwann cells and oligodendrocytes

28
Q

The myelin sheath

A

Longitudinally, myelin sheaths separated by nodes of ranvier, specialise naked axonal areas where APs are proper gated
Myelin sheaths between nodes are internodes

29
Q

Multiple sclerosis: pathophysiology

A

BBB breakdown - damaged BBB drives entrance of immune cells mostly T cells

Chronic inflammation - demyelination triggered by T cells attacking myelin, driving recruitment of other inflammatory cells by releasing cytokines and antibodies. BBB leakage causes swelling, activation of macrophages and cycle of inflammation and damage driven by astrocytes and microglia

30
Q

Multiple sclerosis phase one

A

Immune driven damage
Recognise antigens as foreign (autoimmunity)
Myelin as foreign (MVP) and produce antibodies against them
Access to BBB via menigeal space
Reactivate and accumalate and lead to local damage to BBB and so entrance into brain

31
Q

Multiple sclerosis phase 2

A

Access axons and myelin, attack and remove
Reactivation of T cells, trigger activation of resident glial cells due to inflammatory cells
Degrading myelin, activation of cells, further degradation etc

Migroglia activated by presence of inflammatory factors, engaged into detrimental phenotype and contribute to inflammation. BBB damaged at many points, new activation outlasting initial waves of activation driven by lymphocytes and contribute to axon degradation after myelin
Nt2 - dormant but activates a1 cells that will try to remyelinate

Diagnostic- patients recurrent MRI, demyelinated loci reacurrent, demyelination but never reaches past levels

32
Q

Injury and microglia initial reaction

A

Prolongation and then move body towards to try to contain it

33
Q

Alzheimer’s disease - clinical landscape

A

Amyloid related
Tau relayed
Amyloid and tau
Others - not as common but slowly moving towards it

34
Q

Innate immunity is a driver and/or a cause if AD

A

Infectious stimulus eg flu, batter inflammation- condition accelerated faster
Inflammation disease vs non - greater AD progression (epidemiological studies)
Genome wide associated studies - APP, PSEN1, PSEN2 causes but rare but genetics to do with innate immunity biggest genetic contributor

35
Q

Evidence for contribution of microglia to neurodegen - Parkinson’s

A

Hypothesis - Microbiome and circulating mediators in your blood have ability to change trajectory of PD
Microglia sense this change and do it in the brain
Cross ref with gwas data from Pf and cross ref with single cell expression datasets for all different cell types in the brain (what cell is expressing what)
A lot in neurons, oligodendrocyte lineages (ng2)
Microglia not much going on
So microglia not really relevant to PD

36
Q

Immune roles of microglia

A

Acute neurodegeneration
Chronic neurodegen with extracellular misfolding
Chronic neurodegen with intracellular protein misfolding
So spectrum and then systemic inflammation so switched microglia and specific

Multidimensional integration
Age, species, gender etc

37
Q

Emergence of microglia functional diversity in neurodegen: disease associated microglia (DAM)

A

Single cell sequencing
Small proportion of microglia differentiate into disease associated microglia (DAM)
Baseline state (homeostatic) into DAM based on TREM2, pro inflammatory

Whole microglia and sequenced in bulk
Upreg and downreg
Compare to mouse model and no similarity
Yes microglia changes but different in mice

38
Q

Microglia functional diversity in neurodegen

A

At least 4 microglial subpopulations changing in ad
Profound sec differences
Little correlation with mouse DAM signatures

Later study

39
Q

Microglia functional diversity in neurodegen: ApoE in microg

A

Model of tau pathology
Breed into 8.3 8.4 or 8. Knock out background
Control - degree of degeneration
TE4 - more degen

Follow up paper
Tau 8.4 treat with plx 3397 (inhibitor of Colony stimulating factor 1 receptor)
Microglia Need this to survive and proliferate
Neurodegen not there so E4 drives ad through microglia

40
Q

In neurodegen microglia numbers go up

A

Colony stimulating factor 1 inhibition
Prevent proliferation of microglia
Impeding microglia numbers, the disease progressed slower
Cognition improved

41
Q

ALS

A

Motor neurone disease (spinal cord)
SoD1 (G93) transgenic nice to medial 20% of the familiar cases of ALS
Extensive research and multiple drug trials failed to provide effective treatment
SOD1 - microglia proliferation increased and controlled by CSF1R

42
Q

Blocking CSF 1R activity slows the progression of functional deficits in ALS

A

Better than ALS
Prevent some deficiency
Prolong survival rate

43
Q

CSF1R pathway increased in AD

A

So increased migroglia

Post mortem, AD brains. Increase of CSF1R, SPI1

Increased proliferation of microglia
Microglia around amyloid beta plaques
Therapeutic targeting of CSF1R inhibits microglial proliferation in APp/PS1 mice and shifts the inflammatory profile

44
Q

CSF1R inhibition prevents behavioural deficits observed in APP/PS1 mice without altering AB load

A

T maze
AZ will make choice based on chance
Microglia reduction - based on short term memory

45
Q

Experiments need to be clinically relevant

A

Repurposing the CSF1R inhibitor JNJ527 for AD: target engagement and bio markers
In humans
Autoradiogrophy
pet to image migroglia
Identify proteins in CSF tab

46
Q

Amyloid beta need microglia to cause synaptic generation

A

Tau spreading and synaptic dysfunction not seem as much with reduced microglia numbers

Neurodegenerative (8 decks)

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