Amyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease
| Autor: | Martin A. Bruno, Walter E. Mushynski, A. Claudio Cuello, Guillermina Almazan, Wanda Leon, Gabriela Fragoso |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Male
Nitric Oxide Synthase Type II Minocycline Amyloid beta-Protein Precursor Mice Nerve Growth Factor Aged 80 and over Brain General Medicine Up-Regulation Nitric oxide synthase Matrix Metalloproteinase 9 Neurology Female Alzheimer's disease Genetically modified mouse medicine.medical_specialty Amyloid Mice Transgenic Biology Pathology and Forensic Medicine Cellular and Molecular Neuroscience Downregulation and upregulation Alzheimer Disease Peroxynitrous Acid Internal medicine Reaction Time Extracellular medicine Animals Humans Immunoprecipitation Nerve Growth Factors CD40 Antigens Protein Precursors Cholinergic neuron Maze Learning Aged Amyloid beta-Peptides medicine.disease Peptide Fragments Rats Inbred F344 Rats Disease Models Animal Nerve growth factor Endocrinology nervous system biology.protein Tyrosine Neurology (clinical) |
| Zdroj: | Journal of Neuropathology & Experimental Neurology. 68:857-869 |
| ISSN: | 1554-6578 0022-3069 |
| DOI: | 10.1097/nen.0b013e3181aed9e6 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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