Neuroinflammation Flashcards
What are the major types of non-neuronal cells in the brain
Oligodendrocytes
Astrocytes
Microglia
Ependymal cells
Lymphatics
Cells comprising the BBB
What is the role of oligodendrocytes in the brain
Create myelin for insulating axons and speeding up signal transmission
What is the role of astrocytes in the brain
Support neurons, regulate the BBB, maintain ion balance, and recycle neurotransmitters
What is the role of microglia in the brain
Immune cells of the CNS, clearing debris and regulating inflammation
What is the role of ependymal cells in the brain
Produce and circulate cerebrospinal fluid (CSF).
what is the role of lymphatics in the brain
Clear waste from the brain via the glymphatic system
What is the role of the cells comprising the BBB in the brain
Protect the brain by controlling substance entry while supplying nutrients.
How do astrocytes contribute to the maintenance of homeostasis in the healthy brain?
Regulating the BBB: Controlling nutrient and waste exchange.
Ion and Neurotransmitter Balance: Buffering potassium ions and recycling neurotransmitters like glutamate.
Energy Supply: Providing metabolic support to neurons via glucose and lactate.
Synaptic Function: Modulating synaptic transmission and plasticity.
Repair: Supporting recovery after minor brain injuries.
Describe the blood-brain barrier’s structure. Which non-neuronal cells are involved?
The BBB is a specialised membrane comprised of:
○ endothelial cells with tight junctions
○ Vascular pericytes
○ Perivascular glia
These cells, sometimes referred to as the “neurovascular unit” cooperate to form a selectively permeable barrier
What is the function of the BBB
Regulation of vascular permeability
Limit the entry of leukocytes into the CNS
Protect the CNS from:
§ Fluctuating ion concentrations
§ Circulating neurotransmitters
§ Macromolecules
§ Large proteins such as complement
§ Blood-borne pathogens
What is the role of ependymal cells in cerebrospinal fluid production?
Form the ependyma - thin lining around the ventricles of the brain and spinal canal
Columnar, ciliated cells
Produce cerebrospinal fluid
○ Via the choroid plexus
They also help circulate CSF, ensuring nutrient delivery and waste removal.
How do microglia respond to damage/infection?
Occurs within hours of injury or proinflammatory stimulus
Upregulate
○ Chemokine receptors (enables chemotaxis)
○ Complement receptors
○ Fc receptors (enables phagocytosis of opsonised antigen)
○ MHC proteins and accessory proteins (enables antigen presentation and interaction with infiltrating T-cells)
Produce ROS, NO, proinflammatory cytokines
○ Influence BBB permeability
○ Allow recruitment of adaptive immune cells to the site of infection
Morphological changes
○ Withdraw their long processes
○ Bushy morphology with thickening of proximal processes
Phagocytosis
Compare and contrast M1 and M2 microglial activation states. Why is this classification considered oversimplified?
Historically peripheral macrophages were thought to be either classically activated “M1” macrophages or alternatively activated anti-inflammatory “M2” macrophages
○ There is infact a subtle spectrum of activation states rather than 2 polarised states
○ The same is true of microglia - exposed to IL-1B or LPS in an artificial experimental set up they can become proinflammatory “M1-like” but they’re not normally
Microglia are relatively “repressed” compared with peripheral macrophages
○ Microglia are sheltered from circulating serum proteins by BBB
○ Brain has high levels of TGF-beta
○ Microglia receive inhibitory signals
§ Microglial CD200R (inhibitory receptor with ITIM) on micrglial membrane binds CD200 on neuronal membrane
§ Microglial CX3CR1 (fractalkine receptor) binds CXC3CL1 released by neurons
§ Repressed by neurotransmitters including ACh and GABA
How does chronic neuroinflammation contribute to Alzheimer’s disease progression?
Inflammation is an adaptive sequence of events which occurs in response to trigger and aims to:
○ Remove dead pathogens/dead or damaged cells/debris
○ Repair damage
○ Restore homeostasis
Regulation of the immune response is essential
We often refer to the “dual nature” of neuroinflammation
Initially it is beneficial -> increased plaque clearance however…
In dementia the stimuli for microglial activation include
○ Misfolded proteins
○ Loss of “dampening” signals from neurons
○ Inflammatory mediators
These signals persist! There is no “resolution” stage resulting in…
Chronic inflammation which becomes deleterious
How does microglial priming exacerbate neurodegenerative conditions such as AD?
In the diseased brain microglia are stimulated by pathology associated with disease (we can see this based on morphological change) but they are not M1 like (they have relatively low levels of proinflammatory cytokines)
SUBSEQUENT stimulation with a second inflammatory stimulus (UTI) induces an exaggerated response
- Produce lots of proinflammatory mediators
- Maladaptive reactivation of synaptic pruning
- Withdrawal of normal neurotrophic/neuroprotective support
Explain how microglial activation affects amyloid plaques and tau tangles in AD.
Microglia are found in direct contact with amyloid plaques and tau tangles
Microglia become “activated”
○ Their morphology is altered
○ Their expression profiles change depending on proximity to plaques/tangles
○ They proliferate
○ They release cytokines
○ Microglia are heterogenous and they change over time
What is the role of astrocytes in pathology
“reactive astrogliosis” has historically been visualised via GFAP staining
Glial fibrillary acidic protein (GFAP) is an intermediate filament protein found only in astrocytes
Astrocytes increase GFAP expression -> morphological changes
This led us to some very binary thinking about astrocytes:
○ They’re either “normal” or “reactive”
Why might acute neuroinflammation initially be beneficial in AD?
Can promote the clearance of amyloid-beta plaques and stimulating repair processes through activated microglia and cytokine release
What are the various chronic and acute systemic inflammatory medical conditions that are associated with an increased risk of dementia
Stroke
Diabetes
Midlife hypertension
Midlife obesity
Midlife hypercholesterolaemia
Infection
Systemic inflammation exacerbates cognitive decline
What is TREM2 and why is it a potential target in early AD
Triggering receptor expressed on myeloid cells 2
○ Recognition receptor on microglia
○ Signalling is protective
○ Facilitates microglial activation and clustering around amyloid plaque pathology
○ Is involved in phagocytosis and downregulation of pro-inflammatory cytokines
TREM2 agonism has both improved and exacerbated AD-related pathologies in various animal models
What are the hurdles in the treatment of AD
Diagnosis is not often accurate
Pathology begins >20 years before symptom onset
So how do we know who to treat?
○ Requires identification of those at risk
With what?
○ AD is a heterogenous disease
○ A given drug wont work in all individuals
When?
○ Treatment needs to precede diagnosis
○ Need to identify drugs first then we can optimise the treatment window
How?
○ There is a blood brain barrier breakdown associated with AD however
○ Brain penetrant small molecules?
