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Nerve growth factor metabolic dysfunction in Down’s syndrome brains

M. Florencia Iulita, Sonia Do Carmo, Alison K. Ower, Ashley M. Fortress, Lisi Flores Aguilar, Michael Hanna, Thomas Wisniewski, Ann-Charlotte Granholm, Mona Buhusi, Jorge Busciglio, A. Claudio Cuello
DOI: http://dx.doi.org/10.1093/brain/awt372 860-872 First published online: 11 February 2014

Summary

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.

  • Down’s syndrome
  • Alzheimer’s disease
  • basal forebrain cholinergic neurons
  • proNGF
  • matrix metallo-protease 9
  • Abbreviations
    IOD
    integrated optical density
    MMP2
    matrix metallo-protease 2
    MMP9
    matrix metallo-protease 9
    proNGF
    pro-nerve growth factor
    TIMP1
    tissue inhibitor of metalloproteases
    tPA
    tissue plasminogen activator
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