NGF steers microglia toward a neuroprotective phenotype

Caterina Rizzi, Alexia Tiberi, Michela Giustizieri, Maria Cristina Marrone, Francesco Gobbo, Nicola Maria Carucci, Giovanni Meli, Ivan Arisi, Mara D'Onofrio, Silvia Marinelli, Simona Capsoni, Antonino Cattaneo

Research output: Contribution to journalArticlepeer-review

Abstract

Microglia are the sentinels of the brain but a clear understanding of the factors that modulate their activation in physiological and pathological conditions is still lacking. Here we demonstrate that Nerve Growth Factor (NGF) acts on microglia by steering them toward a neuroprotective and anti-inflammatory phenotype. We show that microglial cells express functional NGF receptors in vitro and ex vivo. Our transcriptomic analysis reveals how, in primary microglia, NGF treatment leads to a modulation of motility, phagocytosis and degradation pathways. At the functional level, NGF induces an increase in membrane dynamics and macropinocytosis and, in vivo, it activates an outward rectifying current that appears to modulate glutamatergic neurotransmission in nearby neurons. Since microglia are supposed to be a major player in Aβ peptide clearance in the brain, we tested the effects of NGF on its phagocytosis. NGF was shown to promote TrkA-mediated engulfment of Aβ by microglia, and to enhance its degradation. Additionally, the proinflammatory activation induced by Aβ treatment is counteracted by the concomitant administration of NGF. Moreover, by acting specifically on microglia, NGF protects neurons from the Aβ-induced loss of dendritic spines and inhibition of long term potentiation. Finally, in an ex-vivo setup of acute brain slices, we observed a similar increase in Aβ engulfment by microglial cells under the influence of NGF. Our work substantiates a role for NGF in the regulation of microglial homeostatic activities and points toward this neurotrophin as a neuroprotective agent in Aβ accumulation pathologies, via its anti-inflammatory activity on microglia.

Original languageEnglish
Pages (from-to)1395-1416
Number of pages22
JournalGlia
Volume66
Issue number7
DOIs
Publication statusPublished - Jul 2018
Externally publishedYes

Keywords

  • Amyloid beta-Peptides/metabolism
  • Animals
  • Brain/cytology
  • CX3C Chemokine Receptor 1/genetics
  • Cells, Cultured
  • Coculture Techniques
  • Green Fluorescent Proteins/genetics
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia/cytology
  • Nerve Growth Factor/administration & dosage
  • Neurons/cytology
  • Neuroprotection/physiology
  • Phagocytosis/physiology
  • Receptors, Nerve Growth Factor/antagonists & inhibitors
  • Synaptic Transmission/physiology
  • Tissue Culture Techniques
  • Transcriptome

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