Amyloid β-Induced Nerve Growth Factor Dysmetabolism in Alzheimer Disease

Abstract

We have reported that the precursor form of nerve growth factor (proNGF) and not the mature NGF is liberated in the CNS in an activity-dependent manner and that its maturation and degradation occurs in the extracellular space by the coordinated action of proteases (Bruno & Cuello, 2006). In this report we communicate evidence for a diminished conversion of the NGF precursor molecule to its mature form as well as evidence for an increased NGF-degradation in Alzheimer’s brain samples. These alterations of the NGF metabolic pathway result in an up-regulation of proNGF levels. In these Alzheimer’s brain samples we have also found that the elevated proNGF occurs largely in a peroxynitrated form. The intrahippocampal injection of Aß-oligomers provoked a similar up-regulation of proNGF in naïve rats, along with microglia activation, increased levels of inducible nitric oxide synthase (iNOS) and hyperactivity of the NGF degrading enzyme MMP-9. The elevated iNOS provoked the generation of biologically inactive; peroxynitrite-modified proNGF in Aß oligomer-injected rats. These parameters were corrected with the application of minocycline. The application of minocycline in a transgenic AD mouse model also diminished altered MMP-9, iNOS and microglial activation, preserving cognitive behavior and normalizing proNGF levels. These effects of Aß amyloid CNS burden on NGF metabolism would explain the well-known and paradoxical up-regulation of proNGF in Alzheimer disease, accompanying by atrophy of forebrain cholinergic neurons.