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P4‐167: Cholinergic Trophic Disconnection in Aging and Alzheimer's Oxidative Damage and NGF Inactivation
Author(s) -
Bruno Martin A.,
Cuello A. Claudio
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.08.226
Subject(s) - nerve growth factor , cholinergic , cholinergic neuron , chemistry , peroxynitrite , basal forebrain , oxidative stress , neurotrophin , medicine , endocrinology , neuroscience , biology , biochemistry , receptor , enzyme , superoxide
Background: an Basal forebrain cholinergic neurons (BFCN) are highly dependent on a continuous supply of biologically active nerve growth factor (NGF). It has been postulated that the cholinergic atrophy observed in aging and in Alzheimer’s disease (AD) is due to diminished NGF supply. However, in AD proNGF is elevated and NGF synthesis is not impaired. Our labs have shown that a compromise in the maturation and degradation of NGF in AD is a major cause for a trophic failure in this disease (Bruno et al, JNEN, 2009). In addition, we have found that in AD endogenous NGF is being targeted by peroxynitrite, a mediator of oxidative damage. Methods: Cortical proNGF/NGF were immuno-precipitated from cortical brain homogenates from AD humans, AD transgenic mouse model and aged and behaviorally characterized rats and resolved with antinytrotyrosine antibodies to reveal nitration of tyrosine residues in proteins. Results: In AD transgenic model and in the hippocampus of naı̈ve rats the accumulation of oligomeric forms of the Ab peptide induced an immediate inflammation along with oxidative stress brain damage and the dysregulation of NGF maturation and degradation; an aspect that explains the vulnerability in AD of cholinergic neurons related to learning and memory processes. Further to that, we have seen that peroxynitrite can cause nitration of tyrosine residues on proNGF molecules and that nitrated proNGF is the predominant molecular form of NGF and its concentration increased in AD brain cortical tissue when compared with age-matched controls. Nitrated proNGF can be converted into nitrated mature NGF, displaying a diminished capacity for inducing TrkA phosphorylation and activation. Cortical proNGF in aged and cognitively impaired rats was also shown to be a target for peroxynitrite-mediated oxidative damage. Conclusions: These studies provide evidence for oxidative stress damage of NGF molecules in brain samples of both aged and cognitively impaired rats and AD human brain. In the case of AD these changes are also accompanied by a compromised maturation of NGF and exacerbated degradation. Acknowledgements: this work is supported by Agencia FONCyT Argentina (PICT 2008-1989) to MAB and Canadian Institutes of Health Research grant # MOP-89360 and the Alzheimer’s Association grant IIRG-0625861 to ACC.