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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    ABSTRACT: We have explored the potential neuroprotective effect of local lentiviraly-mediated overexpression of nerve growth factor (NGF) on in vivo long-term potentiation (LTP) in the rat hippocampus under pathological conditions. The suspension of lentiviral particles was prepared using a genetic construct containing the human NGF gene under the control of a neuron-specific CaMKII promoter. Two weeks after the viral injection NGF concentration in the hippocampus doubled. In vivo recordings of total electrical activity in the dentate gyrus were performed. While the increased expression of NGF did not affect the amplitude of evoked postsynaptic potentials recorded after a high-frequency stimulation of the perforant path, it prevented the LTP decline induced by the i.c.v. administration of 50nM beta-amyloid (25-35) 1h prior to tetanization. Our results demonstrate that increased endogenous NGF concentration can rescue hippocampal neuronal function from beta-amyloid peptide induced impairment. Copyright © 2015. Published by Elsevier B.V.
    Brain research 08/2015; DOI:10.1016/j.brainres.2015.07.051 · 2.83 Impact Factor
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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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    ABSTRACT: The expression of matrix metallo-proteases (MMP-2, MMP-3, MMP-7, and MMP-9), plasminogen and their regulators (TIMP-1, tissue plasminogen activator and neuroserpin) was investigated in cerebrospinal fluid (CSF) from subjective cognitive impairment (SCI) subjects, mild cognitive impairment (MCI), and Alzheimer's disease (AD) cases. ELISA analysis revealed a significant increase in MMP-3 protein levels in CSF from AD subjects, compared to age-matched SCI and MCI cases. No significant differences in MMP-2 and MMP-9 protein levels were detected between the three groups. MMP-7 levels were undetectable in all three groups. MCI individuals exhibited increased levels of the metallo-protease inhibitor TIMP-1 as well as higher plasminogen and neuroserpin expression, compared to SCI subjects. Levels of tissue plasminogen activator (tPA) were significantly reduced in AD CSF. Correlation analysis revealed a significant positive association between MMP-3, p-tau, and total-tau levels. Conversely, there was a significant negative correlation between this protease and Mini-Mental State Examination (MMSE) scores. tPA positively correlated with amyloid-β levels in CSF and with MMSE scores. Our results suggest that MMP-3 and tPA, in combination with current amyloid-β and tau biomarkers, may have potential as surrogate indicators of an ongoing AD pathology.
    Journal of Alzheimer's disease: JAD 02/2014; 40(3). DOI:10.3233/JAD-132282 · 4.15 Impact Factor
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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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    ABSTRACT: Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.
    Brain 02/2014; 137(3). DOI:10.1093/brain/awt372 · 10.23 Impact Factor
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