NGF-Cholinergic Dependency in Brain Aging, MCI and Alzheimers Disease

A.   C.   Cuello; A.      Bruno; K.F.   S.   Bell

Abstract

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 Alzheimers 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.

Keywords: basal forebrain cholinergic neurons, CNS, trophic support system, acetylcholinesterase, amyloid pathology

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