Glial Cells In Neurogen Flashcards
90% of cells in the brain are Glial cells
Do not carry nerve impulses
PNS - schwann cells
CNS - macroglia 85-90% (astrocyte, ependymal cells, Oligodendrocytes) and microglia (10-15%)
Functions of glia
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
Phylogenetically advantage of glial cells
Human 80%
Rat/mice 60%
More complex the brain the more glial
Bigger and more complex astrocyte cells in humans than mice
Development of research into glial cells
New staining mechanisms
Improvements in microscopes
Neurone research progressed quicker than glial research
Neuro glia in PNS
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
Neuro glia in CNS
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
Developmental structures of the brain
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
Time scale of development
Before birth
Neurogenesis
Neuronal migration
Flip genesis and synaptogenesis
After birth
Myelination
Synaptic pruning
Endothelial blood brain barrier with 6 weeks of gestation
Radial glia cells
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)
From o2a astrocytes and Oligodendrocytes
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
Schwann cells
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
Astrocytes
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
Microglia are macrophages but only one of the brains immune population
Research relatively new so immune cells not yet fully understood
Research for microglia
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
Development and maintenance of brains immune toolkit: microglia and non prenchymal brain macrophages
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
Basic characteristics of microglia population
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
Systemic sensing microglia
Survailent microglia
Proliferating microglia
Phagocytosis microglia
Neuromodulatory microglia
Pruning microglia (overshoot, becomes over active in neurodegenerative?)
Nissl staining resulted in discovery of microglia
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
Colonisation and lineages
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
Specification of microglia during development
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
Astrocytes roles
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
Tripartite synapse
~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
Tripartite synapse evidence
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
Blood brain barrier
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
Glial and axonal injury- glial scar
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
Astrocyte subtypes in neurodegenerative
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
Myelinating cells
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
The myelin sheath
Longitudinally, myelin sheaths separated by nodes of ranvier, specialise naked axonal areas where APs are proper gated
Myelin sheaths between nodes are internodes
Multiple sclerosis: pathophysiology
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
Multiple sclerosis phase one
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
Multiple sclerosis phase 2
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
Injury and microglia initial reaction
Prolongation and then move body towards to try to contain it
Alzheimer’s disease - clinical landscape
Amyloid related
Tau relayed
Amyloid and tau
Others - not as common but slowly moving towards it
Innate immunity is a driver and/or a cause if AD
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
Evidence for contribution of microglia to neurodegen - Parkinson’s
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
Immune roles of microglia
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
Emergence of microglia functional diversity in neurodegen: disease associated microglia (DAM)
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
Microglia functional diversity in neurodegen
At least 4 microglial subpopulations changing in ad
Profound sec differences
Little correlation with mouse DAM signatures
Later study
Microglia functional diversity in neurodegen: ApoE in microg
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
In neurodegen microglia numbers go up
Colony stimulating factor 1 inhibition
Prevent proliferation of microglia
Impeding microglia numbers, the disease progressed slower
Cognition improved
ALS
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
Blocking CSF 1R activity slows the progression of functional deficits in ALS
Better than ALS
Prevent some deficiency
Prolong survival rate
CSF1R pathway increased in AD
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
CSF1R inhibition prevents behavioural deficits observed in APP/PS1 mice without altering AB load
T maze
AZ will make choice based on chance
Microglia reduction - based on short term memory
Experiments need to be clinically relevant
Repurposing the CSF1R inhibitor JNJ527 for AD: target engagement and bio markers
In humans
Autoradiogrophy
pet to image migroglia
Identify proteins in CSF tab
Amyloid beta need microglia to cause synaptic generation
Tau spreading and synaptic dysfunction not seem as much with reduced microglia numbers
