Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease.
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.
Bruno
Martin A
MA
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Leon
Wanda C
WC
Fragoso
Gabriela
G
Mushynski
Walter E
WE
Almazan
Guillermina
G
Cuello
A Claudio
AC
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use; D020932:Nerve Growth Factor / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D030421:Peroxynitrous Acid / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D019013:CD40 Antigens; D009414:Nerve Growth Factors; D010446:Peptide Fragments; D011498:Protein Precursors; C075222:amyloid beta-protein (1-42); C514218:pro-nerve growth factor, rat; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D020932:Nerve Growth Factor; D052247:Nitric Oxide Synthase Type II; D020780:Matrix Metalloproteinase 9; D008911:Minocycline