title: Histamine induces the production of matrix metalloproteinase-9 in human astrocytic cultures via H1-receptor subtype.
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 Ca(2+) 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.
authors: Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, 530 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors: Aarti
authors: A
authors: Patel
authors: Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, 530 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors: Vishnu
authors: V
authors: Vasanthan
authors: Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, 530 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors: Wen
authors: W
authors: Fu
authors: Department of Biochemistry, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors: Richard P
authors: RP
authors: Fahlman
authors: Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, 530 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
authors: David
authors: D
authors: MacTavish
authors: Division of Neurology, Department of Medicine, Institute of Neuroscience and Mental Health, 530 Heritage Medical Research Centre, University of Alberta, Edmonton, AB, T6G 2S2, Canada. jack.jhamandas@ualberta.ca.
authors: Jack H
authors: JH
authors: Jhamandas
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006632:Histamine / Q000008:administration & dosage / Q000502:physiology*; D017442:Histamine Agonists / Q000008:administration & dosage; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D017442:Histamine Agonists; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; D006632:Histamine; D011493:Protein Kinase C; D019950:Mitogen-Activated Protein Kinase 1; D020780:Matrix Metalloproteinase 9
keywords: Astrocytes; Histamine; Matrix metalloproteinase-9; Soluble oligomeric amyloid beta peptide