Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease - Nature Neuroscience

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• perivascular macrophages

• ice-cold FACS buffer (PBS, 2% FBS, 0.78 mM EDTA)

• Absence of Spp1 expression in AD mouse models results in prevention of synaptic loss.

• perivascular SPP1 induces microglial phagocytic states

• phosphoprotein 1 (SPP1/osteopontin) is upregulated predominantly by perivascular macrophages

• what signals drive a

• microglia and perivascular macrophages (PVMs)

• engulfment of synapses and axon tracts

• We quantified internalized level of Homer1-immunoreactive synaptic puncta within CD68+ P2Y12+ microglial lysosomes

• phagocytic microglia–synapse interactions

• multiple autocrine and paracrine signaling pathways to be potentially modulated by perivascular SPP1

• C1q, the initiating protein of the classical complement cascade that mediates microglial phagocytosis of synapses

• microglia and PVMs could potentially influence each other to coordinate phagocytosis in response to central nervous system perturbations

• environmental cues that modulate potential microglial functional states are poorly understood

• intercellular and intracellular mechanisms governing this impairment remain unclear

• (SPP1/osteopontin), predominantly derived from PVM, as an extrinsic modulator of microglial phagocytosis

• 10–14 µm for all on-slide IHC experiments

• a 63 × 1.4-NA objectiv

• 60–80 z-stack planes were taken with 0.27-μm spacing

• background subtraction of Homer1 channel.