Amyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease

We previously reported that the precussor form of nerve growth factor (pro-NGF) and not mature NGF is liberated in the CNS ill all activity-dependent manner, and that its maturation and degradation occur in the extracellur space by the coordinated action of proteases. Here, we present evidence of diminished conversion of proNGF to itsmature from 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 proNGF 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 ill a transgenic mouse AD model. The effects of amyloid-beta amyloid CNS burden oil NGF metabolism may explain the paradoxical upregulation of pro-NGF in AD accompanied by atrophy of forebrain cholinergic neurons.