Article

Amyloid β-induced nerve growth factor dysmetabolism in Alzheimer disease

Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Journal of Neuropathology and Experimental Neurology (Impact Factor: 4.37). 09/2009; 68(8):857-69. DOI: 10.1097/NEN.0b013e3181aed9e6
Source: PubMed

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.

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    • "It has been shown that neurotrophins, especially NGF and BDNF, can have a neuroprotective effect in AD-like conditions (Wang et al., 2002; Skaper, 2008; Bruno et al., 2009). NGF injection prevents degeneration of cholinergic neurons after fornix lesion or administration of toxins (Williams et al., 1986; Koliatsos et al., 1990; Charles et al., 1996; Blesch et al., 2005; Skaper, 2008). "
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    • "Equally significant is the observation that MMP‐3 has been shown to activate certain MMPs, including MMP‐9 [17]. Increased MMP‐9 activation occurs in AD and MCI brains [18] [19], compromising the endogenous levels of the neurotrophin nerve growth factor (NGF) as it is its main degrading protease [20]. In AD brains, the extracellular metabolism of NGF is also affected at the level of its precursor, proNGF. "
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    • "MMP9 is the main mature NGF degrading enzyme (Bruno and Cuello, 2006). In post-mortem Alzheimer's disease brains, we have shown that there is accumulation of proNGF as a result of a failure in its maturation, as well as increased MMP9 activity (Bruno et al., 2009a). Notably, these changes are also present in mild cognitive impairment brains, a stage in which the increase in proNGF and MMP9 activity positively correlates with the degree of pre-mortem cognitive decline (Peng et al., 2004; Bruno et al., 2009b). "
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