Neuroinflammation Flashcards
What factors contribute to neuroinflammation?
Ageing as misfolded proteins occur
Environmental and genetic factors.
Vascular components, such as strokes, and small vessel diseases, such as hypertension, also contribute.
Microglia
Microglia are essential for: neurogenesis, synaptogenesis, synaptic pruning, NT modulation, disposing of cell debris and proteins.
If they are activated into the pro-inflammatory state for too long, they become cytotoxic.
The M1 state of microglia is pro-inflammatory. These release cytokines and interleukins, which impact on neuronal function and cause cytotoxicity.
The M2 activated state is neuroprotective.
Microglia are the resident macrophages in the CNS and represent 10-15% of the cell population in the brain.
In the steady-state condition, microglia can be identified using several common markers which they share with macrophages, such as GFAP, CD11β, CD45, CD68 and CX3CR1.
Microglia actively survey their surroundings and can rapidly respond to environmental changes such as an immune threat. They can become activated and undergo morphological changes to become phagocytic to remove the encountered threat. Morphological changes are accompanied by expression and secretion of inflammatory molecules such as cytokines and chemokines, which help microglia communicate with astrocytes and peripheral immune cells.
Microglia are involved in pruning of unnecessary synapses, which is important in maintaining CNS homeostasis. Over- or under-pruning leads to abnormal neuronal network formation and impaired synaptic development.
Neurodegeneration
AD → extracellular Aβ aggregates, intracellular tau tangle formation, and hippocampal and cortical neurodegeneration.
Tau and FUS are present in frontotemporal dementia.
Pd → intracellular α-synuclein aggregates (Lewy bodies) and dopaminergic neurodegeneration.
All of these factors can lead to microglial activation. Acute inflammation can be beneficial, but chronic inflammation is harmful.
Alzheimer’s
TNF-α is induced by Aβ and tau→ impacts Aβ metabolism and plays roles in neuroinflammation-mediated cell death.
IL-6 is induced by Aβ and tau → impacts on APP processing. Over expression induces gliosis and suppresses Aβ deposition.
IL-18 is sometimes decreased, sometimes increased in AD. Overexpression increases microglia activation and plaque phagocytosis.
IL-1β is an important mediator of the inflammatory response, involved in cell proliferation, differentiation and apoptosis.
The BBB can be damaged. This causes neuroinflammation in the brain due to vascular dysfunction, speeding up toxic processes such as protein misfolding.
Immunostaining showed that microglia surround Amyloid plaques and try to engulf the misfolded proteins to remove them. Under healthy conditions, acute microglia activation is involved in Aβ uptake and clearance, having a neuroprotective effect.
Ischemia
After a stroke, M1 microglia initiate a proinflammatory response, causing neuroinflammation and neurodegeneration → increased expression of IL-1β, IL-6, TNFα, and the microglial M1 surface marker CD16/32, without hippocampal neuronal cell loss
M2 microglia initiate an anti-inflammatory response, leading to neurogenesis, angiogenesis and the release of trophic factors.
Phytochemicals block M1 differentiation and release of inflammatory mediators, resulting in neuroprotection and ischemic recovery.
Extracellular zinc, released from hippocampal neurons in response to brain ischaemia, triggers morphological changes in microglia, triggering M1 differentiation. Zinc chelators can prevent this activation of microglia.
Depression
The PFC regulates neural circuity of mood, including the amygdala and DA neurons projecting from the VTA to the NAc.
Resting microglia regulate the circuity of mood.
In MDD, hyperactivation of neuronal circuit induces M1 polarisation, resulting in dysfunction of nerve fibres initiating in the PFC and hypoactivation of 5-HT neurons projecting from raphe nucleus to the PFC.
Schizophrenia
M1 microglia activation correlates with the peaks in schizophrenia symptoms.
Abnormal pruning affects early brain development and may contribute to SZ.
Immune activation, genes and stress contribute to microglia activation. This causes an imbalance of excitation and inhibition.
Synapse density is reduced in postmortem cortical tissue from SZ patients → increased synapse pruning.
Incubating neurons with patient-derived induced microglia-like cells (iMG) causes a decrease in synaptic number. Microglia derived from schizophrenia patients prune synapses much faster than those derived from healthy controls.
Microglia CXCR1 receptor mutations
Deficiencies of the microglial receptor CX3CR1 impair functional development of thalamocortical synapses.
These are associated with schizophrenia and ASD.
Fractalkine (CX3CL1) is a chemokine produced by neurons which instructs microglia on neuronal and synaptic maturation. Its CX3CR1 receptor is only expressed by microglia and controls their migration and function. This is the ONLY receptor through which microglia receive input from neurons.
Mutations cause signalling dysfunction and decrease the release of neuroprotective factors like BDNF, increasing pruning.
Knock-outs of this gene show an altered ratio of NMDA and AMPA receptors.
Neuroinflammation and microglia polarisation
Cytokines polarise microglia to unique phenotypes on a spectrum towards more M1- or M2-like.
Upon chronic inflammation, an overabundance of inflammatory cytokines skews microglial polarisation towards the M1 phenotype. M1 microglia, in turn, produce additional inflammatory cytokines, generating a cycle.
This skewed population of M1 microglia exhibits impaired phagocytosis and is cytotoxic in, for example, Alzheimer’s disease and multiple sclerosis.
Treating neuroinflammatory diseases
Therapeutic agents, such as glatiramer acetate, bexarotene, and PPARγ agonists, have been used.
These inhibit inflammation and induce M2 activation, resulting in reduced disease severity.
Prion disease
Mice inoculated with the misfolded prion protein became terminally ill, showing synapse loss, memory loss, behavioural defect, impacted protein synthesis and eventually death.
Strong M1 activation was seen.
iNOS generates nitric oxide, which induces neurotoxicity if activated for too long. This is affected in prion disease, producing much more NO than necessary. This causes S-nitrosylation (reversible) or nitrotyrosination (irreversible) of proteins, inducing protein dysfunction.
Amyloid-β proteins are nitrotyrosinated → initiation of protein aggregation in AD.
NOS inhibition prevents the decline in glutamatergic transmission, preventing the decline in EPSP amplitude caused by neurodegeneration. The synapse response is recovered.
