Abstract
Basal forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) supply for the maintenance of their cholinergic phenotype as well as their cholinergic synaptic integrity. The precursor form of NGF, proNGF, abounds in the CNS and is highly elevated in Alzheimer’s disease. In order to obtain a deeper understanding of the NGF biology in the CNS, we have performed a series of ex vivo and in vivo investigations to elucidate the mechanisms of release, maturation and degradation of this neurotrophin. In this short review, we describe this NGF metabolic pathway, its significance for the maintenance of basal cholinergic neurons, and its dysregulation in Alzheimer’s disease. We are proposing that the conversion of proNGF to mature NGF occurs in the extracellular space by the coordinated action of zymogens, convertases, and endogenous regulators, which are released in the extracellular space in an activity-dependent fashion. We further discuss our findings of a diminished conversion of the NGF precursor molecule to its mature form in Alzheimer’s disease as well as an augmented degradation of mature NGF. These combined effects on NGF metabolism would explain the well-known cholinergic atrophy found in Alzheimer’s disease and would offer new therapeutic opportunities aimed at correcting the NGF dysmetabolism along with Aβ-induced inflammatory responses.
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Acknowledgements
This work was supported by Canadian Institutes of Health Research grant # MOP-89360 and the Alzheimer’s Association to A. C. C.; W. L. is the recipient of a Fellowship from the University of Los Andes, Venezuela; M. F. I. is the recipient of the McGill University Provost’s Graduate Fellowship; and A. C. C. is the holder of the McGill University Charles E. Frosst Merck Chair of Pharmacology.
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Proceedings of the XIII International Symposium on Cholinergic Mechanisms
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Cuello, A.C., Bruno, M.A., Allard, S. et al. Cholinergic Involvement in Alzheimer’s Disease. A Link with NGF Maturation and Degradation. J Mol Neurosci 40, 230–235 (2010). https://doi.org/10.1007/s12031-009-9238-z
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DOI: https://doi.org/10.1007/s12031-009-9238-z