AUTHOR=Tiberi Alexia , Carucci Nicola Maria , Testa Giovanna , Rizzi Caterina , Pacifico Paola , Borgonovo Giulia , Arisi Ivan , D’Onofrio Mara , Brandi Rossella , Gan Wen-Biao , Capsoni Simona , Cattaneo Antonino 

TITLE=Reduced levels of NGF shift astrocytes toward a neurotoxic phenotype

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 11 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2023.1165125

DOI=10.3389/fcell.2023.1165125

ISSN=2296-634X

ABSTRACT=The nerve growth factor (NGF) is critical for neuronal physiology during development and adulthood. Despite the well-recognized effect of NGF on neurons, less is known about whether this molecule can actually affect other cell types in the central nervous system (CNS). In this work, we show that astrocytes are susceptible to changes in ambient levels of NGF. First of all, we observe that tampering with NGF signaling in vivo via the constitutive expression of an antiNGF antibody induces astrocytic atrophy. A similar asthenic phenotype is encountered in an uncleavable-proNGF transgenic mouse model (TgproNGF#72 mice), effectively increasing the brain proNGF levels. To dissect whether this effect on astrocytes is cell-autonomous, we cultured wild-type primary astrocytes in the presence of antiNGF antibodies, uncovering that a short incubation was sufficient to potently and rapidly trigger calcium oscillations. The acute induction of calcium oscillations by antiNGF antibodies was followed by progressive morphological changes similar to those observed in antiNGF AD11 mice. Conversely, incubation with mature NGF had no effect on either calcium activity nor on astrocytic morphology. At longer timescales, transcriptomic analysis revealed that NGF-deprived astrocytes acquire a proinflammatory profile. In particular, antiNGF treated astrocytes show an upregulation of neurotoxic transcripts and a downregulation of neuroprotective mRNAs. Consistent with that data, culturing wild-type neurons in the presence of NGF-deprived astrocytes led to neuronal cell death. Finally, we report that in both awake and anesthetized mice, astrocytes in layer I of the motor cortex respond with an increase in calcium activity to acute NGF inhibition using either NGF neutralizing antibodies or a TrkA-Fc NGF scavenger. Moreover, in vivo calcium imaging in the cortex of the 5xFAD neurodegeneration mouse model shows an increased level of spontaneous calcium activity in astrocytes, which is significantly reduced after the acute administration of NGF. In conclusion, we unveil a novel neurotoxic mechanism driven by astrocytes, triggered by their sensing, and reacting to, changes in the levels of ambient NGF.