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: 3.8). 09/2009; 68(8):857-69. DOI: 10.1097/NEN.0b013e3181aed9e6
Source: PubMed


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 · 2.84 Impact Factor
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    • "The literature data indicate the relation of IL-6 with BDNF expression in neurons (Bartkowska et al., 2010). A large body of evidences indicates that reduced expression of neurotrophins and changes in the level of their receptors can lead to dysregulation of neuronal function, and neuronal death can lead to the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Scaper 2008; Bruno et al. 2009; Calissano et al. 2010). Therefore, the possibility to upregulate the level of neuroprotective substances, such as NGF, BDNF, and IL-6 is one of the key aspects to improve nervous system development and function, and can be a promising goal in the therapy of neurodegenerative diseases , in which a decreased level of neurotrophins is observed (Lessmann et al. 2003; Aloe et al. 2012; Allen et al. 2013). "
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    ABSTRACT: Neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor, as well as cytokines, for example, interleukin-6 (IL-6) play an important role in neuroprotection and in the control of the central nervous system (CNS) function. Reduced expression of neurotrophic factors can lead to dysregulation of neuron function and neuronal death. There is also evidence for mutual interactions between neurotrophins and IL-6. Therefore, the up-regulating the level of neuroprotective substances is one of the key manners to control the nervous system development and function. It can be a promising aim in the therapy of neurodegenerative disease in which the decreased level of neurotrophins is observed. In our recent studies, the role of proline-rich polypeptide complex (PRP) and its nonapeptide fragment (NP) in the regulation of neurotrophic activity in cultured astrocytes was shown. PRP and NP stimulate human astrocytoma cell line U87 to release the significant amounts of NGF to the extracellular space both in its precursor and mature form. We also provide the evidence that in NP-treated cells, the level of βNGF mRNA was increased. NP-treated cells used in this study produced also increasing amounts of IL-6. This finding indicates that PRP and its nonapeptide fragment NP up-regulate neurotrophic activity of U87 cell line by increase of NGF synthesis and its release into the extracellular space. It was also shown that NP-dependent increased production of IL-6 can enhance the NGF activity.
    Cellular and Molecular Neurobiology 04/2015; 35(7). DOI:10.1007/s10571-015-0192-8 · 2.51 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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