SP21 Ageing microglia

SP21 Microglia ageing: friend or foe to synaptic plasticity

Project leader: Otto W. Witte

Background and previous work
The exact role of microglia in age-associated learning deficits is still unclear. Our previous work showed an increased level of inflammatory cytokines in the ageing brain, and this probably contributes to the impairment of brain plasticity. Microglia as the major cell producing neurotoxic and neuroprotective cytokines may thus be the primary driver of impaired plasticity in the aged brain. Understanding changes in microglia due to ageing and impact on synaptic plasticity could help in developing strategies designed to enhance microglia cell function and/or to slow or prevent microglial dysfunction leading to novel approaches toward neurodegenerative disease prevention and treatment.

Specific aims and working programme
We recently showed in vitro that long-term cultures and increased cell proliferation induce changes in telomere length and telomerase activity in microglia, associated with a senescent cell phenotype. Therefore we hypothesise that similar changes occur in microglia during normal ageing. We will compare microglia derived from neonatal animals with those derived from adult (3 months), old (12 month) and very old (24 months) animals in terms of changes in telomere length, telomerase activity, production of neurotrophic factors and cytokines by using qPCR, Q-FISH and ELISA. DNA damage will be analysed using y-H2AX and 53BP1 immunofluorescence. In parallel, epigenetic reprogramming of microglial cells in ageing brain will be analyzed. Effects on microglia ageing on neuron survival, synapse formation and pruning will be investigated in vitro by co-cultures or in vivo by depleting microglia using a mice model previously described. Effect of microglia depletion on neuronal function will be analyzed by electrophysiology and using small mouse 9.4 Tesla MRI. At the same time effect of microglia ageing on learning will be analysed on a behavioural level by specifically inducing DNA damage in microglia and thus mimicking the ageing phenotype.