Cholinergic neurons of the basal forebrain are considered the main target cell of Nerve Growth Factor in the CNS, despite the fact that also astrocytes display NGF receptors. However, the potential effects of NGF on astrocytes have not been investigated extensively.

Here we show that deprivation of the mature form of NGF in mice expressing neutralizing antibodies (AD11 mice) induces in an age-dependent manner, a marked astrocytic atrophy. To understand the role of p75NTR and proNGF in astrocytic atrophy, we analyzed these cells in p75NTR -/- mice, in p75NTR -/- crossed to anti-NGF mice (AD12 mice) and in mice over-expressing an uncleavable form of proNGF. We found that, while the morphology of astrocytes was unchanged in p75NTR-/- mice, the overexpression of proNGF determines an astrocytic atrophy similar to that found in AD11 mice. The degeneration is worsened in AD12 mice, with the formation of GFAP-immunoreactive intracellular inclusions.

Astrocytes are important for their ability to influence neuronal activity. Here, we show that NGF deprivation, concomitantly to astrocytic atrophy, also determines a decrease in synaptic markers expression.

Thus, we show that NGF plays a significant role in the maintenance of astrocyte functions in vivo. We postulate that astrocytic atrophy plays a causal role in the broad neurodegeneration induced by NGF deprivation in anti-NGF mice, which goes well beyond the expected effects on its neuronal targets.