Microglia are immune cells that monitor our brain and degrade unhealthy neurons and excess synapses. In Alzheimer’s disease (AD) however, microglia excessively destroy synapses, marking them as enticing treatment targets. AD patients accumulate cortical Amyloid-beta (Aβ) plaques and neurofibrillary tau tangles, whilst losing neurons and synapses, and consequently: memory and cognition. Microglia are the brain’s immune cells, mediate neuroinflammation, continuously monitor their surrounding cells, and prune (eliminate) excess synapses during development. Interestingly, various AD risk genes are highly expressed in- or linked to- microglia, and while “activated” microglia can clear Aβ, they also degrade neurons and synapses. Our knowledge on microglia function mainly stems from rodent studies, which show microglia can target synapses via complement molecules or fractalkine, but we do not know exactly which proteins mediate this contact, how this translates to humans, and how this is affected in AD.
I hypothesize that microglia use different cell surface proteins to interact with synapses in AD, compared to a healthy brain. By combining several cutting-edge technologies, I can now test this hypothesis in living, human microglia. I will transplant human iPSC-derived microglial progenitors into the cortex of healthy- and APPNLGF mice, to ensure the microglia develop a transcriptional- and morphological state like human in vivo microglia (expertise of the Mancuso lab). Using TurboID proximity labeling and quantitative high-resolution mass spectrometry, I will tag-, extract-, and identify the proteins at the microglia-synapse interaction site and determine how they differ from the AD mouse model (expertise of the De Wit lab). Given that abnormal microglial function is linked to various neurodegenerative diseases, my work will both provide valuable fundamental knowledge on microglial-synapse interactions and contribute to the development of new AD treatment targets.
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme