Neuroinflammation Flashcards
Microglia roles and the causes/consequences of neuroinflammation overview
Microglia are main immunocomponent cells of brain. they colonise CNS in prenatal development and slowly self-renew. account for 0.5-15% of total cell pop in brain. Have different phenotypes depending on the CNS microenvironment. They produce neurotoxic factors to damage debris/aggregates/foreign bodies.
Neuroinflammation plays role in depression, neurodegeneration and dementia. Cerebrovascular and small vessel diseases contribute to neuroinflammation
Can also be induced by amyloid-beta and cytokines being absorbed from the blood - gut-brain axis can play a role in the pathology.
Protein misfolding examples for different diseases
Caused by genetic mutations and environmental factors. no treatments that can prevent/cure. Neuroinflammation is both a cause and a consequence of these protein folds.
AD: amyloid-beta and tau
PD: alpha-synuclein
Amyotrophic lateral sclerosis: SOD-1, TDP-43, and FUS
Huntington’s: HTT (huntingtin)
All current treatments for these aim of removing the proteins, or by modulating ACh and glutamate transmission.
Microglia mediated neuroinflammation
Activated microglia (by immunogenicity/pathogens) leads to the production of cytokines, chemokines, and other compounds (that will contibute to neuroinflammation). If the pathogen/tissue repair cannot be completed, it can lead to chronic activation of the microglia, and the acute inflammation will become chronic neuroinflammation. This can ultimately lead to neurone death.
The microglia rapidly respond to environmental changes. Once activated they undergo morphological changes to become phagocytic. This is accompanied by the release of the chemicals mentioned above.
They are activated and play a role in neurodegeneration in AD, frontotemporal dementia, and PD.
Microglia activated forms and key compounds released
Can be activated (depending on the pathway of activation) into somewhere on the spectrum of M1 or M2 microglia. M1 are inflammatory, while M2 are anti-inflammatory. Will release different compounds in response to activation depending on the form they have been activated into.
The M2 phenotype favours tissue remodelling/repair and angiogenesis. Largely mediated by TGF-beta (transforming growth factor).
The M1 phenotype is more for defense agains pathogens and tumours, leads to loss of neurones. Releases TNF-a (which causes necrosis and apoptosis) and IL-1beta (which is a key mediator of the inflammatory response).
Microglia released compounds role in AD
M1 compounds:
IL-6 is released to suppress amyloid-beta deposition, which means it will be released more in AD, consequently also releasing more of the other M1-phenotype compounds.
TNF-a is induced by amyloid-beta and tau proteins, and plays large role in neuroinflammation-mediated cell death. It also increases amyloid-beta synthesis
IL-1Beta increases amyloid-beta synthesis
IL-18 increases APP production, consequently increasing amyloid-beta synthesis.
Effect on microglia following CNS ischameia
Ischemia trigger the release of zinc from hippocampal neurones, which triggers microglia to morphologically change. See increased expression of IL-1B, IL-6, and TNF-a - indicates M1 activation.
When zinc was removed, microglia were not activated, indicating zinc as having an essential role in microglia activation
Depression and schizophrenia: microglia
M1 microglia phenotype activated in MDD. inhibits 5-HT synthesis, and causes neuroinflammation. This induces dysfunction in the nerves projecting between the prefrontal cortex and the neural circuitry
schizophrenia symptoms seen to occur in line with the proportion of M1 activity. Heightened microglial activity - role in pathology not fully understood
Microglia polarisation in chronic inflammation and potential treatment
Chronic inflammation leads to the polarisation of microglia more towards M1 phenotype.
To treat diseases associated with this phenotype, treatments aim to skew the polarisation back towards M2. E.g., PPARgamma agonists.
Nitrergic role in neuroinflammation
Low [NO] associated with pro-survival, whereas high [NO] can lead to cell death.
Microglia activation seen to produce INOS (inducible), to produce high amounts of NO, mediating neuronal cytotoxicity. Heightened iNOS associated with huntingtin aggregation
The NO can then react with other components in neurones, e.g., the reversible reaction to produce 5-nitrothiols, and irreversibly to produce nitrotyrosine (which exacerbates amyloid-B aggregation). These can be cytotoxic.
NOS inhibitors tested to prevent decline in glutamatergic transmission associated with pathology. Recovers synaptic response.
