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while sparing their axonal input, resulted in atrophy, but not cell death, of the NGF-dependent cholinergic neurons of the medial septum, unequivocally demonstrating that NGF in the adult is key for the maintenance of neuronal phenotype, but not survival (Sofroniew et al. 2001). A similar NGF-dependency for the phenotypic characteristics of cholinergic neurons of the nucleus basalis has also been amply documented (Cuello 1994). Further confirmation of the essential role of NGF in the maintenance of the CNS cholinergic phenotype in the mature brain is provided by the evidence that blocking "endogenous" NGF function through the application of either antibodies mapping out the ligand (NGF) or NGF mimetic peptides with antagonist actions over the receptor (TrkA) in the cerebral cortex of adult rats results in the loss of preexisting cortical cholinergic synapses (Debeir et al. 1999). Such an observation indicates that the "steady-state" number of CNS cholinergic synapses is dependent on a continuous supply of endogenous NGF, in line with the classical Hebbian concept that brain activity unleashes a

Nerve Growth Factor. Fig. 4. Schematic representations of events leading to proNGF conversion into mNGF and its degradation. Neuronally stored proNGF, plasminogen, tPA, neuroserpin, proMMP-9, and TIMP-1 would be released into the extracellular space upon neuronal stimulation. Released tPA would induce the conversion of plasminogen to plasmin, where its activity is tightly regulated by secreted neuroserpin. The generated plasmin would convert proNGF into mature NGF and activate proMMP-9 into active MMP-9. Mature NGF would interact with its cognate receptors (TrkA and p75N activated MMP-9. (From Bruno and Cuello 2006. PNAS; with author's and publisher's permission.)

) or suffer degradation by growth-dependent synaptic efficacy. While the evidence for a target-derived action of NGF is strong, it is not clear whether endogenous NGF can also act in a paracrine fashion. However, it has been shown both in rodents and primates that exogenously applied NGF can also act in a paracrine fashion (Tuszynski et al. 2005), a concept (see below) which might have therapeutic applications.

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