Neuroimmune system in health and disease

Positive aspects of neuroinflammation

• reorganization of host priorities

• Enhanced plasticity

• Tissue repair

• Neuro-protection

Negative aspects of neuroinflammation

• collateral damage

• Anxiety & depression

• Cognitive impairment, reduced plasticity

• Neuronal damage

How do microglia prune synapses during development

• express many phagocytic receptors, have increases lysosomal activity & participate in synaptic pruning

• weaker synapses are tagged by complement proteins which then are bound by complement receptors on microglial processes

• activated microglia Phagocytose weakened synapse

*also prune via a chemokines based mechanism

• crosstalk with astrocytes

How are astrocytes involved in synaptic pruning

• can prune during development by engulfing weak synapses via phagocytic receptors which detect complement proteins

• they activate microglia

Summarize the role of neuroimmune system in schizophrenia

Neuroinflammation-induced changes in microglia are implicated in schizophrenia pathogenicity

• altered microbiome can lead to alterations in microglia stricture and function

• Reduced mitochondria

• Immature phenotype associated with altered development

MIA (maternal immune activation) can induce disease associated “dark microglia” in schizophrenia

Neuroinflammation alters glutamergic brain circuits in schizophrenia through:

• enhanced complement-mediated engulfment of excitatory synapses

• Production of autoantibodies against NMDARs (N-methyl-D-aspartate receptor)

• Changes in glutamate homeostasis due to alterations in astrocytes

How does inflammation affect the protein plaques of Alzheimer’s

Protein plaques:

• AB plaques activate microglia & trigger their pro-inflammatory signaling pathways

• Pro-inflammatory activity of microglia can cause increase in AB production

How does inflammation affect the neurofibrillary tangles of AD

Neurofibrillary tangles

• TAU phosphorylation can be caused by production of AB plaques

• TAU phosphorylation can also be caused by increased inflammatory signaling

• TAU hyper phosphorylation & tangles can also increase inflammatory signaling

How does inflammation affect neurodegeneration of AD?

• neural debris from this can stim. microglia

• Can be caused by excessive microglial response

• Microglia cause an sig. amount of synaptic loss, most likely through dysfunctional pruning

• Complement cascade profoundly unregulated by amyloid plaques

• *chronic neuroinflammation also leads to loss of synaptic associated proteins