LC 4 - microglia in neurodegeneration

Question 1

pruning

Answer 1

removing of weak/unused synapses by microglia to improve network efficiency and efficacy

Question 2

synapses in neurological diseases

Answer 2

o AD, stress, anxiety, schizophrenia: fewer synapses and dendrites
o ASD: more synapses, fewer dendrites
Due to under/over pruning

• Different diseases use the same pathological mechanisms that lead to different phenotypes
  o Schizophrenia and AD both have decreased amounts of synapses
• Maternal immune activation is a risk factor for ASD and schizo

Question 3

microglia in AD

Answer 3

• ~25% of the ± 84 AD risk genes (GWAS) have enriched or exclusive expression in microglia and/or are linked to immune function.
  o ligand activators (IL34),
  o immune receptors (TREM2, MS4A4A, HLA-DQA1 & CD33),
  o signalling intermediates (PLCG2, PTK2B & INPP5D)
  o pathogenic immune responses and cell mechanisms such (CR1 & CLU)
  o cytoskeletal machinery (ABI3, EPHA1 and FERMT2)

Question 4

neurodamage and microglia

Answer 4

• Microglia are very dynamic and can change phenotype (become reactive – various types - and become neutral again)
• ABI3 risk factor AD –> cytoskeleton links to microglial function/motility
  o Also links to DISC1 –> modulates motility and pruning of microglia and astrocytes
• Microlesion - homeostasis
  1. Resident microglia respond to and cloak tissue microlesion
  2. Neutrophils or other immune cells are required to the tissue
  3. Cloaking prevent them from contacting the lesion
  4. The attracted cells cannot activate and induce inflammation
• Macrolesion – inflammation
  1. Resident microglia respond to and attempt to cloak tissue microlesion
  2. Neutrophils are attracted and contact the lesion (due to insufficient cloaking)
  3. Contact neutrophil undergoes inflammatory death
  4. More neutrophils are requited by this
  5. Swarm- initiation: neutrophil-driven inflammation and tissue damage ensues

Question 5

neurodevelopment and microglia

Answer 5

• Early microglia (hematopoietic stem cells from the yolk sac) migrate into the neural tube and assist in angiogenesis and neurogenesis
• Involved in various processes in all stages of neurodevelopment
• Prenatal
  o Promote cell death
  o Promote fasciculation
  o Limit axon outgrowth
• Perinatal
  o Support neuronal survival
  o Promote cell death
   Phagocytosis
• Postnatal
  o Promote synapse maturation and remodelling
  o Pruning
  o Promote OPC survival and differentiation

Question 6

pruning and complement

Answer 6

• Microglia help synaptic remodelling: leads to forming strong synapses and pruning
• Complement system marks weak synapses for pruning
• tgfbeta released by astrocytes causes self expression of C1q on presynaptic axon terminal which leads to C3 production at the synapse
• Also occurs in neurodegeneration
  o Complement mutations and abnormalities are linked to excessive pruning in various neurodevelopmental/degenerative diseases
   In schizophrenia increased C4 (and others) is seen at synapses
• Besides complement (phosphatidyl serine works in hippocampus and cortex) other systems facilitate pruning