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G\u00e9n\u00e9ral des Alpes Maritimes","award":["ALZ201912009627"],"award-info":[{"award-number":["ALZ201912009627"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["FVA-FR20067"],"award-info":[{"award-number":["FVA-FR20067"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["MT5-AD"],"award-info":[{"award-number":["MT5-AD"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["ANR-22-C18-0024-01"],"award-info":[{"award-number":["ANR-22-C18-0024-01"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["AMX-19-IET-004"],"award-info":[{"award-number":["AMX-19-IET-004"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["ANR-17-EURE-0029"],"award-info":[{"award-number":["ANR-17-EURE-0029"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["ALZ201912009627"],"award-info":[{"award-number":["ALZ201912009627"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["FDT202001011017"],"award-info":[{"award-number":["FDT202001011017"]}]},{"name":"Conseil G\u00e9n\u00e9ral des Alpes Maritimes","award":["FDT201904008423"],"award-info":[{"award-number":["FDT201904008423"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer\u2019s disease (AD)\u00a0in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1\u03b2)-mediated neuroinflammation and A\u03b2 production in primary Tg immature neural cell cultures after 11 days in vitro. We now investigate the effect of MT5-MMP on incipient pathogenic pathways that are activated in cortical primary cultures at 21\u201324 days in vitro (DIV), during which time neurons are organized into a functional mature network. Using wild-type (WT), MT5-MMP\u2212\/\u2212 (MT5\u2212\/\u2212), 5xFAD (Tg), and 5xFADxMT5-MMP\u2212\/\u2212 (TgMT5\u2212\/\u2212) mice, we generated primary neuronal cultures that were exposed to IL-1\u03b2 and\/or different proteolytic system inhibitors. We assessed neuroinflammation, APP metabolism, synaptic integrity, and electrophysiological properties using biochemical, imaging and whole-cell patch-clamp approaches. The absence of MT5-MMP impaired the IL-1\u03b2-mediated induction of inflammatory genes in TgMT5\u2212\/\u2212 cells compared to Tg cells. Furthermore, the reduced density of dendritic spines in Tg neurons was also prevented in TgMT5\u2212\/\u2212 neurons. IL-1\u03b2 caused a strong decrease in the dendritic spine density of WT neurons, which was prevented in MT5\u2212\/\u2212 neurons. However, the latter exhibited fewer spines than the WT under untreated conditions. The spontaneous rhythmic firing frequency of the network was increased in MT5\u2212\/\u2212 neurons, but not in TgMT5\u2212\/\u2212 neurons, and IL-1\u03b2 increased this parameter only in Tg neurons. In terms of induced somatic excitability, Tg and TgMT5\u2212\/\u2212 neurons exhibited lower excitability than WT and MT5\u2212\/\u2212, while IL-1\u03b2 impaired excitability only in non-AD backgrounds. The synaptic strength of miniature global synaptic currents was equivalent in all genotypes but increased dramatically in WT and MT5\u2212\/\u2212 neurons after IL-1\u03b2. MT5-MMP deficiency decreased endogenous and overexpressed C83 and C99 levels but did not affect A\u03b2 levels. C99 appears to be cleared by several pathways, including \u03b3-secretase, the autophagolysosomal system, and also \u03b1-secretase, via its conversion to C83. In summary, this study confirms that MT5-MMP is a pivotal factor affecting not only neuroinflammation and APP metabolism but also synaptogenesis and synaptic activity at early stages of the pathology, and reinforces the relevance of targeting MT5-MMP to fight AD.<\/jats:p>","DOI":"10.3390\/biom14121645","type":"journal-article","created":{"date-parts":[[2024,12,23]],"date-time":"2024-12-23T04:33:29Z","timestamp":1734928409000},"page":"1645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Suppression of MT5-MMP Reveals Early Modulation of Alzheimer\u2019s Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice"],"prefix":"10.3390","volume":"14","author":[{"given":"Dominika","family":"Pilat","sequence":"first","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Paumier","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Louis","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Manrique","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Garc\u00eda-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Stephan","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Bernard","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00eblle","family":"Pardossi-Piquard","sequence":"additional","affiliation":[{"name":"IPMC, UMR 7275 CNRS-UCA, INSERM U1323, Labex DistAlz, 06560 Valbonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2098-1750","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Checler","sequence":"additional","affiliation":[{"name":"IPMC, UMR 7275 CNRS-UCA, INSERM U1323, Labex DistAlz, 06560 Valbonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Khrestchatisky","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4088-8238","authenticated-orcid":false,"given":"Eric","family":"Di Pasquale","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e9vin","family":"Baranger","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-2712","authenticated-orcid":false,"given":"Santiago","family":"Rivera","sequence":"additional","affiliation":[{"name":"Inst Neurophysiopathol, CNRS, INP, Aix-Marseille Univ, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1007\/s00018-019-03178-2","article-title":"Metalloproteinases and Their Tissue Inhibitors in Alzheimer\u2019s Disease and Other Neurodegenerative Disorders","volume":"76","author":"Rivera","year":"2019","journal-title":"Cell. 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