Mouse and human microglial phenotypes in Alzheimer’s disease are controlled by plaque phagocytosis through HIF1α

Grubman A1, Choo XY1, Chew G2, Ouyang JF2, Sun G1, Croft NP1, Rossello F1, Simmons R3, Buckberry S3, Vargas Landin D3, Pflueger J3, Vandekolk TH1, Abay Z1, Chan J1, Haynes J1, Williams S1, Chai S1, Wilson T4, Lister R3, Pouton CW1, Purcell A1, Rackham O2, Petretto E2 and Polo JM1

  1. Monash University, Clayton, Australia.
  2. Duke NUS, Singapore.
  3. University of Western Australia, Perth, Australia. MHTP Medical Genomics Facility, Clayton Australia.

Microglia are brain immune cells that remove cellular and extracellular debris and regulate synaptic plasticity, maturation and removal. Recently altered microglial genomics, epigenomics and functions emerged as key contributors to Alzheimer disease (AD). Nonetheless, whether toxic microglial inflammatory cytokine secretion and aberrant synapse overpruning outweigh the beneficial amyloid clearance functions of microglia in AD remains highly controversial. To address these questions, we explored whether functional differences in amyloid plaque phagocytosis in a plaque-depositing AD mouse result from or contribute to the underlying molecular and functional diversity of microglia in AD. Using a combination of bulk and single cell RNA-seq, and proteomics approaches, we showed that the amyloid plaque phagocytic subset of microglia are molecularly distinct from physiological microglia and from non-plaque containing microglia in AD brains. For instance, several later onset AD risk factors and their direct interacting partners are differentially expressed in plaque-containing microglia. We are now using stem cell derived microglia like cells to manipulate the signaling pathways involved in generating the plaque-associated microglial signature.