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Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease.
J Neuropathol Exp Neurol. 2009 Aug; 68(8):857-69.JN

Abstract

We previously reported that the precursor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS in an activity-dependent manner, and that its maturation and degradation occur in the extracellular space by the coordinated action of proteases.Here, we present evidence of diminished conversion of pro-NGF to its mature form and of greater NGF degradation in Alzheimer disease (AD) brain samples compared with controls. These alterations of the NGF metabolic pathway likely resulted in the increased pro-NGF levels. The pro-NGF was largely in a peroxynitrited form in the AD samples. Intrahippocampal injection of amyloid-beta oligomers provoked similar upregulation of pro-NGF in naive rats that was accompanied by evidence of microglial activation (CD40), increased levels of inducible nitric oxide synthase, and increased activity of the NGF-degrading enzyme matrix metalloproteinase 9. The elevated inducible nitric oxide synthase provoked the generation of biologically inactive, peroxynitrite-modified pro-NGF in amyloid-beta oligomer-injected rats. These parameters were corrected by minocycline treatment. Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels in a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden on NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons.

Authors+Show Affiliations

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19606067

Citation

Bruno, Martin A., et al. "Amyloid Beta-induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease." Journal of Neuropathology and Experimental Neurology, vol. 68, no. 8, 2009, pp. 857-69.
Bruno MA, Leon WC, Fragoso G, et al. Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease. J Neuropathol Exp Neurol. 2009;68(8):857-69.
Bruno, M. A., Leon, W. C., Fragoso, G., Mushynski, W. E., Almazan, G., & Cuello, A. C. (2009). Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease. Journal of Neuropathology and Experimental Neurology, 68(8), 857-69. https://doi.org/10.1097/NEN.0b013e3181aed9e6
Bruno MA, et al. Amyloid Beta-induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease. J Neuropathol Exp Neurol. 2009;68(8):857-69. PubMed PMID: 19606067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease. AU - Bruno,Martin A, AU - Leon,Wanda C, AU - Fragoso,Gabriela, AU - Mushynski,Walter E, AU - Almazan,Guillermina, AU - Cuello,A Claudio, PY - 2009/7/17/entrez PY - 2009/7/17/pubmed PY - 2009/9/2/medline SP - 857 EP - 69 JF - Journal of neuropathology and experimental neurology JO - J Neuropathol Exp Neurol VL - 68 IS - 8 N2 - We previously reported that the precursor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS in an activity-dependent manner, and that its maturation and degradation occur in the extracellular space by the coordinated action of proteases.Here, we present evidence of diminished conversion of pro-NGF to its mature form and of greater NGF degradation in Alzheimer disease (AD) brain samples compared with controls. These alterations of the NGF metabolic pathway likely resulted in the increased pro-NGF levels. The pro-NGF was largely in a peroxynitrited form in the AD samples. Intrahippocampal injection of amyloid-beta oligomers provoked similar upregulation of pro-NGF in naive rats that was accompanied by evidence of microglial activation (CD40), increased levels of inducible nitric oxide synthase, and increased activity of the NGF-degrading enzyme matrix metalloproteinase 9. The elevated inducible nitric oxide synthase provoked the generation of biologically inactive, peroxynitrite-modified pro-NGF in amyloid-beta oligomer-injected rats. These parameters were corrected by minocycline treatment. Minocycline also diminished altered matrix metalloproteinase 9, inducible nitric oxide synthase, and microglial activation (CD40); improved cognitive behavior; and normalized pro-NGF levels in a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden on NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons. SN - 0022-3069 UR - https://www.unboundmedicine.com/medline/citation/19606067/Amyloid_beta_induced_nerve_growth_factor_dysmetabolism_in_Alzheimer_disease_ L2 - https://academic.oup.com/jnen/article-lookup/doi/10.1097/NEN.0b013e3181aed9e6 DB - PRIME DP - Unbound Medicine ER -