Brain Structure and Function

, Volume 221, Issue 4, pp 1845–1860 | Cite as

Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype

  • Aarti Patel
  • Vishnu Vasanthan
  • Wen Fu
  • Richard P. Fahlman
  • David MacTavish
  • Jack H. Jhamandas
Original Article

Abstract

Accumulation of β-amyloid (Aβ) protein within the brain is a neuropathological hallmark of Alzheimer’s disease (AD). One strategy to facilitate Aβ clearance from the brain is to promote Aβ catabolism. Matrix metalloproteinase-9 (MMP-9), a member of the family of Zn+2-containing endoproteases, known to be expressed and secreted by astrocytes, is capable of degrading Aβ. Histamine, a major aminergic brain neurotransmitter, stimulates the production of MMP-9 in keratinocytes through the histamine H1 receptor (H1R). In the present study, we show that histamine evokes a concentration- and calcium-dependent release of MMP-9 from human astrocytic U373 cells and primary cultures of human and rat astrocytes through the H1R subtype. Activation of H1R on astrocytes elevated intracellular levels of Ca2+ that was accompanied by time-dependent increases in MAP kinase p44/p42 and PKC. In-cell western blots revealed dose-dependent increases in both enzymes, confirming involvement of these signal transduction pathways. We next investigated the extent of recombinant human MMP-9 (rhMMP-9) proteolytic activity on soluble oligomeric Aβ (soAβ). Mass spectrometry demonstrated time-dependent cleavage of soAβ (20 μM), but not another amyloidogenic protein amylin, upon incubation with rhMMP-9 (100 nM) at 1, 4 and 17 h. Furthermore, Western blots showed a shift in soAβ equilibrium toward lower order, less toxic monomeric species. In conclusion, both MAPK p44/p42 and PKC pathways appear to be involved in histamine-upregulated MMP-9 release via H1Rs in astrocytes. Furthermore, MMP-9 appears to cleave soAβ into less toxic monomeric species. Given the key role of histamine in MMP-9 release, this neurotransmitter may serve as a potential therapeutic target for AD.

Keywords

Histamine Matrix metalloproteinase-9 Astrocytes Soluble oligomeric amyloid beta peptide 

Supplementary material

429_2015_1007_MOESM1_ESM.eps (4.4 mb)
Supplementary Fig. 1 Gelatin zymogram showing histamine-induced upregulation of Pro-MMP-9 production was not blocked in a concentration-dependent manner following 24 h pre-incubation with H2R (Ranitidine HCl) and H3R (Clobenpropit HCl) antagonists (2.5–100 µM dose range) (EPS 4463 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Aarti Patel
    • 1
  • Vishnu Vasanthan
    • 1
  • Wen Fu
    • 1
  • Richard P. Fahlman
    • 2
  • David MacTavish
    • 1
  • Jack H. Jhamandas
    • 1
  1. 1.Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health530 Heritage Medical Research Centre, University of AlbertaEdmontonCanada
  2. 2.Department of BiochemistryUniversity of AlbertaEdmontonCanada

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