Neuroinflammation Flashcards
Explain the CNS innate immune response
- Microglia are the main immunocomponent cells of the brain
- Microglia can account for 0.5-15% of differet anatomical regions of the brain.
- CNS microenvironment sig shapes microglia phenotype (Dynamic)
How do microglia work?
- Patrol a set area for damage to cells/debris/aggregates
- Produce neurotoxic factors to become damaging
- Imp role in dev and maintaing CNS homeostasis
GIve an overview of neruoinflammation
Triangle shows much larger part of neuroinflammation
Ability to decrease gets worse with age
What are protein misfoldings and how do they cause neurodegenerative diseases?
- Genetic mutations and environmental factors
- No disease preventing treatments
- Past efforts focused on removal of misfolded protein and mod ACh and GLUT transmission
- Common mechanism is Neuroinflammation: Cause and consequence
Why is Neuroinflammation the brains best defence?
- Resting microglia sense and patrol brain
- Once sense changes in the brain they become activated
- Activated they produce lots of cyto+Chemokines etc
- This helps microglia communicate with astrocytes and peripheral immune cells
What happens in chronic activation of microglia?
Cause chronic inflammation, which damages neurons
This leads to the cycle repeating and getting worse and worse etc.
What are microglia?
- Resident macrophages of CNS
- Actively survey surroundings and rapidly respond to any threat
- Upon exposure to endogenous stimuli, microglia become activated and undergo morphological changes to become phagocytic
What are the 2 types of activated microglia?
- Pro-inflammation M1
- Anti-inflammation M2
2 ways to activate microglia
AND
Can change states based on environment in the brain
Explain how neurodegeneration involves microglia?
Alzheimer’s Disease
* Extracellular AB aggregates
* Intracellular tau tangle formation
* Hippocampal and cortical neurodegenerations
* Activates Microglia
Frontotemporal dementia
* Tau
* FUS (Fused in Sarcoma)
* Activates microglia
Parkinson’s
* Intracellular a-synuclein aggregates
* Lewy bodies
* Dopaminergic neurodegeneration
* Activates microglia
What is very important in a healthy brain?
- Healthy brain, but also in many disease, It is important where balance lies between anti and pro - inflammatory microglia
- M1 leads to defence against pathogens and tumour cells, but also causes loss of neurones (TNF-a is released which leads to necrosis or apoptosis)
- M2 leads to the promotion of tissue remodelling/repair and causes angiognesis
What are cytokinin functions?
- TNF-a: Key roles in neuroinflammation-mediated cell death
- IL-6: overexpression induces gliosis and suppresses Aß deposition
- IL-18: overexpression increases microglia activation and increases plaque phagocytosis
- IL-1b: mediatory of the inflammatory response, and involved in cell proliferation, differentiation, and apoptosis
What happens in ADs with cytokines?
Aß remains, the activated stages remain, which continues to enhance neuroinflammation
- Microglia don’t return to resting state.
Why is zinc necessary?
- Extracellular zinc is released (hippocampual neurons) in response to brain ischaemia
- This triggers a morphological change in microglia
How are microglia involved in depression?
- Prefrontal cortex reg neuronal circuitry of mood including amygdala and dopamine neurons proj from VTA to NAc
- MDD: Hyperactivation of neural circuitry, this induces M1 polarisation of microglia
- Resulting in dysfunction of nerve fibers between prefrontal cortex and neural circuitry
- AND hypoactivation of 5-HT neurons proj from raphe nucleus to prefrontal cortex
What is the Nitrergic signalling cascade?
- An action potential causes calcium to enter the neurone via glutamatergic receptors, which causes the production of nitric oxide via nNOS
- Nitric oxide is important in many processes (trafficking, gene expression, diffusion, S-Nitrosylation, and ONNO formation)
- Pro-inflammatory cytokines activate microglia which overexpress iNOS, which shifts the balance of the produced NO to these post-translational modifications, and less so of the physiological NO signalling
- During these conditions, the concentrations of NO are drastically enhanced
