Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer's disease parietal cortex

doi:10.1016/S0169-328X(96)00193-3

Molecular Brain Research

Volume 42, Issue 1, November 1996, Pages 175-178

https://doi.org/10.1016/S0169-328X(96)00193-3 Get rights and content

Abstract

Nerve growth factor (NGF) mRNA and protein levels were determined in parietal cortex samples from both normal and Alzheimer's disease (AD) patients. NGF protein levels were slightly elevated in AD patients compared to controls, but NGF mRNA levels were unchanged in the same tissue samples. Thus, small but reproducible increases in NGF protein reported in AD cortex do not result from increases in NGF mRNA.

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Correlation analysis revealed a significant positive association between BDNF mRNA levels and cognitive performance at early stages (r = 0.626; p = 0.001, Supplementary Fig. 1). Thus, consistent with previous findings of NGF and BDNF deregulation in Alzheimer's disease and Down syndrome (Bruno et al., 2009a; Fahnestock et al., 2001; Fahnestock et al., 1996; Goedert et al., 1986; Iulita et al., 2014b; Michalski and Fahnestock, 2003; Peng et al., 2004; Peng et al., 2005), McGill APP transgenic rats exhibit an accumulation of cortical proNGF without significant changes in NGF mRNA, in parallel with marked reductions in BDNF mRNA expression that correlate with global cognitive deficits. As expected from human studies (Fahnestock et al., 1996; Goedert et al., 1986; Jette et al., 1994), there was no difference in cortical NGF mRNA expression between APP transgenic rats and non-transgenic (wild type) rats at any time point examined (Fig. 2A–C, t-test, p > 0.05; 3–6 months, WT n = 16 and APP +/+ n = 13, 13–15 months, WT n = 13 and APP +/+ n = 14 and 18–21 months, WT n = 6 and APP +/+ n = 7).
Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.
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Citation Excerpt :
The post-mortem brain from AD patients showed a deficit in the cascade responsible for the conversion of pro form of NGF (pro-NGF) into mature NGF (Bruno et al., 2009). The levels of NGF and pro-NGF were found to be significantly elevated in the frontal cortex (Hellweg et al., 1998; Hock et al., 2000; Pedraza et al., 2005; Peng et al., 2004; Podlesniy et al., 2006), parietal cortex (Fahnestock et al., 1996; Podlesniy et al., 2006) and cerebrospinal fluid (Blasko et al., 2006) of AD patients. In our study, treatment with minocycline reversed the increase in the levels of NGF.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder associated with amyloid-β peptide misfolding and aggregation. Neurotrophic factors, such as nerve growth factor (NGF), can prevent neuronal damage and rescue the cholinergic neurons that undergo cell death in AD, reverse deposition of extracellular amyloid plaques and improve cognitive deficits. However, NGF administration is hampered by the poor pharmacokinetic profile of the therapeutic protein and its inability to cross the blood-brain barrier, which requires specialised drug delivery systems (DDS) for efficient NGF delivery to the brain. This review covers the main therapeutic approaches that have been developed for NGF delivery targeting the brain, from polymeric implants to gene and cell-based therapies, focusing on the role of nanoparticulate systems for the sustained release of NGF in the brain as a neuroprotective and disease-modifying approach toward AD. Lipid- and polymer-based delivery systems, magnetic nanoparticles and quantum dots are specifically addressed as promising nanotechnological strategies to overcome the current limitations of NGF-based therapies.
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The homodimer NGF (nerve growth factor) exerts its neuronal activity upon binding to either or both distinct transmembrane receptors TrkA and p75^NTR. Functionally relevant interactions between NGF and these receptors have been proposed, on the basis of binding and signaling experiments. Namely, a ternary TrkA/NGF/p75^NTR complex is assumed to be crucial for the formation of the so-called high-affinity NGF binding sites. However, the existence, on the cell surface, of direct extracellular interactions is still a matter of controversy. Here, supported by a small-angle x-ray scattering solution study of human NGF, we propose that it is the oligomerization state of the secreted NGF that may drive the formation of the ternary heterocomplex. Our data demonstrate the occurrence in solution of a concentration-dependent distribution of dimers and dimer of dimers. A head-to-head molecular assembly configuration of the NGF dimer of dimers has been validated. Overall, these findings prompted us to suggest a new, to our knowledge, model for the transient ternary heterocomplex, i.e., a TrkA/NGF/p75^NTR ligand/receptors molecular assembly with a (2:4:2) stoichiometry. This model would neatly solve the problem posed by the unconventional orientation of p75^NTR with respect to TrkA, as being found in the crystal structures of the TrkA/NGF and p75^NTR/NGF complexes.

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¹: Present address: Program in Physical Therapy, Barry University, 11300 NE 2nd Ave., Miami Shores, FL 33161, USA.

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Short communicationNerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer's disease parietal cortex

Abstract

Neurosci. Lett.

Brain Res.

Mol. Brain Res.

Mol. Brain Res.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

Exp. Mol. Pathol.

Detection of NGF-like activity in human brain tissue: increased levels in Alzheimer's disease

J. Neurosci.

Short communication
Nerve growth factor mRNA and protein levels measured in the same tissue from normal and Alzheimer's disease parietal cortex