NGF-Cholinergic dependency in brain aging, MCI and Alzheimer's disease

Forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) for phenotype maintenance. We have established that in addition to "target-derived" NGF neurotrophic stimulation, cholinergic neurons also respond dose-dependently, to intra-parenchymal NGF administration in the somato-dendritic region of the nucleus Basalis [1], thus illustrating the potential of alternative reparative therapies which would by-pass the undesirable effects of diffuse neurotrophin application. Moreover, our lab has also observed that the steady-state number of cortical cholinergic synapses is dependent on continuous NGF supply, as anti-NGF monoclonal antibodies and TrkA receptor antagonists deplete pre-existing cholinergic bouton numbers [2]. Furthermore, the application of either NGF or TrkA NGF-mimetic agonists successfully rescues the age-dependent loss of cortical cholinergic boutons in aged-impaired rats [3]. The vulnerability of the cortical cholinergic system has also been demonstrated in transgenic animal models of the Alzheimer's disease (AD) amyloid pathology [4-6]. It is of interest to note however, that an up-regulation of cholinergic presynaptic boutons has been observed in certain transgenic mouse models prior to plaque formation [6]. This observation is similar to the visibly increased immunoreactivity of cortical and hippocampal choline acetyltransferase (ChAT) fibers in patients with Mild Cognitive Impairment (MCI, [7]). A series of ex-vivo experiments conducted by our group have demonstrated that contrary to popular belief, proNGF, as opposed to mature NGF, is released from the cerebral cortex in an activity-dependent manner. In addition, proNGF appears to be released with a series of pro-enzymes and enzymes, which are involved in its subsequent maturation to NGF and degradation in the extracellular space [8]. Given that proNGF is known to be upregulated in AD patients [9] a dysregulation in the maturation or degradation of mature NGF might explain the preferential vulnerability of the cholinergic system in the AD pathology.