Glial cells in neurodegeneration Flashcards
There is systemic sensing of microglia. What are the roles of the microglia in a healthy brain?
Brief history of microglia
- Rio Hortega “fountains of microglia”
- Assumed origin from circulating monocytes, until first experiments testing this hypothesis by 90’s
- Experimental models largely confounding the origin on microglia until 2010
- “Golden era” of microglial biology?
Tell me about the colonisation and lineages of the macrophages and what they all arise from
- Erythromyeloid progenitors (EMPs) derived from Yolk Sac give rise to all macrophage populations
- The brain is colonised directly (without relay in the liver) and earlier than other organs
- yolk sac is extraembryonic element
- yolk sac progenitor’s aka. EMP can enter circulation
LO
- Describe the timing and steps of the developmental formation of the individual glial cell types in the nervous system.
- Provide an overview of the different lineages of glial cells, and the critical factors defining lineage commitment and differentiation.
- Describe the functions played by the different glial cell types in the adult and ageing nervous system.
- Describe and give examples of critical roles of glial cells in brain disorders like Alzheimer’s disease, Multiple Sclerosis or SCI. Discuss the contribution of glial cell activation to the progression of brain disorders.
What are the neuroglia found in the PNS and CNS and their roles?
What are some astrocytes functions?
- Neurogenesis and gliogenesis in the adult brain
- Neuronal guidance in development: role of radial glia
- Regulation of synaptogenesis and synaptic maturation in development? (See Chung et al., 2013)
- Structural function: microarchitecture of the brain. Astrocytes define and connect domains that include neurons, synapses, and blood vessels. Communication through gap junctions
- Creation of the blood-brain barrier (astrocytes are main component of this)
- Synaptic modulation
What are roughly 60% of axon-dendritic synapses surrounded by?
Astroglial membranes (hippocampus)
What are the most frequent type of synapses and what are they enwrapped by?
80% of large, perforated synapses (the most frequent type) are enwrapped by astrocytes
With the example of the cerebellum tell me about what purkinje cells interact with the the enwrapping of synapses here and the number
Example of the cerebellum, interaction of Purkinje cells with Bergmann cells (astrocytes of the cerebellum), each cell (astrocytes) enwrapping 2000-6000 synaptic contacts
What type of cells are astrocytes and in response to presynaptic or postsynaptic stimulation, what do they do?
Astrocytes are excitable cells: in response to presynaptic or postsynaptic stimulation, astrocytes can produce transient changes in their intracellular calcium concentrations through release of calcium stores from the ER
coordinated manner between astrocytes via gap junctions
What else can astrocytes influence?
Astrocyte signalling can influence distal synapses that aren’t connected to the originally stimulated synapse
How do astrocytes communicate?
Astrocytes communicate bidirectionally with neurons: able to detect neurotransmitters and other signals released from neurons at the synapse and can release their own neurotransmitters or gliotransmitters (e.g., ATP) that are, in turn, capable of modifying the electrophysiological excitability of neurons
What is the blood-brain barrier?
Barrier between the intracerebral blood vessels and the brain parenchyma (anything protected by BBB)
What forms the BBB?
Formed by tight junctions between endothelial cells and astroglial endfeet
Where is the BBB present, and what is an exception to this?
Present throughout the brain except circumventricular organs (CVOs), neurohypophysis, pineal gland, subfornical organ and lamina terminalis, involved in neuroendocrine signalling (these areas need more flow usually involved in endocrine function)
Compare the structure of the brain capillary and the peripheral capillary
When there is glia and axonal injury, what things can form and tell me about these?
- cystic cavity forms overtime from injury (empty areas where all cells die and full of cystic fluid which is all the dead cells and their tissue)
- astrocytes try to limit spread of injury by forming a glial scar (astrocytes become reactive and hypertrophic)
- but these scars remain in chronic phase
What astrocyte subtypes can form in neurodegenration?
- not understood how astrocytes know which path to take in whether to become A1 and A2
- unknown how many and when they change
- but in basal state, in reaction to specific disorders, they will get specific phenotypes which can be toxic or help with protection
What is the myelinating cell in the CNS and PNS and tell me their ratio?
Oligodendrocytes (all myelinating) in CNS, each myelinating multiple axons (average ~10 axons per cell)
Schwann Cells (myelinating and non-myelinating). Myelinating Schwann cells wrap single axons (1:1)
What is myelination dependent on?
Myelination is dependent on axonal diameter (and viceversa).
Tell me about the radial growth of axon and the myelin sheath
The radial growth of axons (axon’s diameter) and the myelin sheath (number of lamellae) are interdependent, resulting in the g-ratio of axons: number of myelin lamellae (1:10), which is a constant in the CNS and PNS for oligodendrocytes and schwann cells
Tell me about the interdependence of glia-axons
Interdependence of glia-axons: the loss of axons results in degeneration of oligodendrocytes and de-differentiation of Schwann cells; conversely, axons degenerate in the absence of appropriate support from Schwann cells and oligodendrocytes.
Longitudinally, what are myelin sheaths separated by and tell me about these
Longitudinally, myelin sheaths are separated by nodes of Ranvier: specialised naked axonal areas where action potentials are propagated. Myelin sheath between nodes called internodes
Tell me about the pathophysiology of multiple sclerosis
autoimmune disorder. produce antibodies against proteins of myelin
BBB breakdown: damaged BBB drives the entrance of immune cells, predominantly 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 a vicious cycle of inflammation and damage driven by astrocytes and microglia
Tell me what happens early in MS
- Soluble mediates recruit immune cells –> promote inflammation at distal sites
- T cell reactivation by choroid plexus and meningeal APCs
- Perivascular immune cell accumulation
- Vessel activation
- Phagocytosis
What happens in late MS?
- Meningeal tertiary lymphoid-like structures promote glia limitans damage and astrocyte dysfunction
- neuroaxonal and ODC damage and death
- Neurodegeneration processes promote further damage at distal sites
What do the microglial do to help with surveillance?
- Keep position of cell constant through life. Microglial look after a small territory
- Microglia react to ATP and remove it to prevent any damage that could occur
- Microglia are the first cells that react to damage in any condition
What are included on the different phases of clinical trials and tell me about this an alzheimers disease
phase 1: control populations
phase 2: target disease population (under 100)
phase 3: larger target disease population (thousands)
nothing in phase 3 would mean that it is a success so with things being in the middle here shows that it wasn’t successful
can’t stop cognitive decline in these patients
What is innate immunity a driver and/or cause of?
How has this been shown?
Alzheimers disease
epidemiological studies
- inflammation can stick to brain and modify cognitive trajectory
GWAS
- genes with genetic association to disease
What is some evidence for the contribution of microglia to neurodegeneration: Parkinson’s
- neuroinflammation could be a modified trajectory of disease
- altered microbiome; signals back to brain and then leads to the activation of microglia
- microglia are not the solution for PD
What are the immune roles of microglia?
stimulus, magnitude of stimulus, age of induvial, type of diseases etc. determines the microglia states that arise from basal state
can be modulated from systemic information
Tell me about the emergence of microglial functional diversity in neurodegeneration
Disease-associated microglia (DAM)
- subpopulation of microglia that don’t appear in healthy situations. these are called DAMs
- in AD, DAMs are association with Abeta plaques
Tell me about microglial functional diversity in neurodegeneration: DAMs? HAMs?
2019 was first experiments, so very recent
- somebody sequenced trans genomic microglia profile in human brain
- used single cell RNA sequencing technique to do it
- identified that abnormal regulation of genes in microglia which have an overlap with mice with disease
- APOE increase which is a GWAS
second study (on right) used a different approach which sequenced whole microglia population as a combined population. they were very different in AD Vs control brains.
- second comparison between human and mouse. seen no match. activation profile of AD in mouse and human brain. led to further studies
Tell me about microglia functional diversity in neurodegeneration: ApoE in microglia
ApoE is a gene that held strong
took model of Tau pathology and crossed onto mice harbouring different variations of APOE
APOE4= degeneration of brain
combined with drug, that depletes microglia, is signal dependent on microglia? if they do same experiment in brain without microglia, they do not see generation.
Tells you that APOE4 effect on Tau pathology is dependent on microglia
repeated all of this but in astrocytes, they saw the same effect. APOE4 –> drives activation of astrocytes –> microglia –> …
What tend to happen with microglia during neurodegenerative diseases?
common expansion of number of microglia
microglia proliferation up to 10-fold in prion disease brain
microglia replicate 3-4 fold in other diseased brains
if stop microglia proliferation then can understand pathology in disease
What could therapies target for chronic neurodegeneration?
Target microglial proliferation in chronic neurodegeneration
Why is prion disease a good model of chronic neurodegeneration?
- fatal progressive neurodegenerative disease
- predictable spread of pathology
- accumulation of a misfolded amyloid protein
- Neuronal degeneration
- Gliotic response
Tell me about the chronic administration of GW2580
The inhibition of the tyrosine kinase activity of CSF1R inhibits microglial proliferation during prion disease and decreases neurodegeneration
behaviour experiments on mice helps to know the pathology going on in the brain and the effect it has
Tell me about the progressive nervous system disease Amyotrophoic lateral sclerosis (ALS)?
Motor neuron disease (mainly spinal cord)
SOD1 (G93) transgenic mice to model 20% of the familiar cases of ALS
SOD1 is a mutation that appears in humans as well
Extensive research and multiple drug trials failed to provide effective treatment (only Riluzole has modest effect)
What does the blocking of CSF1R activity slow?
The progression of the functional deficits in ALS
Tell me another effect that blocking CSF1R activity has in ALS?
A neuroprotective effect, extending the survival of SODI (G93) mice
What disease is the expression of CSFR1 upregulated in?
Alzheimer’s disease
What is microglial proliferation increased in?
Alzheimer’s disease and APP/PS1 mice
What does the therapeutic targeting of CSFR1 inhibit in APP/PS1 mice and what does it shift?
It inhibits microglial proliferation and shifts the inflammatory profile
CSF1R inhibition prevents the behavioural deficits observed in APP/PS1 mice without altering what?
The Abeta load
What does the therapeutic targeting of CSF1R prevent the degeneration of in APP/PS1 mice?
synaptic degeneration
What does JNJ527 inhibit and prevent?
It inhibits microglial proliferation and activation, preventing conversion of microglia into a DAM phenotype
It prevents Tau-mediated neurodegeneration in P301s mice
When repurposing the CSF1R inhibitor JNJ527 for Alzheimer’s disease, whats needed?
need biomarkers in humans to see if drugs engaging with target and to see how neuroinflammation is progressing
TSPO is a ligand that used for PET imaging in humans
measure CSF of humans to see of something is working, gives biomarker
gives signature of proteins that change
What is microglia a necessary transducer of?
Abeta pathology
