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In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1\u03b2)-mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP\/IL-1\u03b2 tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To test this hypothesis, we used 11\u201314\u00a0day in vitro primary cortical cultures from wild type, MT5-MMP\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      , 5xFAD and 5xFAD\/MT5-MMP\n                      <jats:sup>\u2212\/\u2212<\/jats:sup>\n                      mice, and evaluated the impact of MT5-MMP deficiency and IL-1\u03b2 treatment for 24\u00a0h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>5xFAD cells showed higher levels of MT5-MMP than wild type, concomitant with higher basal levels of inflammatory mediators. Moreover, MT5-MMP-deficient cultures had strong decrease of the inflammatory response to IL-1\u03b2, as well as decreased stability of recombinant IL-1\u03b2. The levels of amyloid beta peptide (A\u03b2) were similar in 5xFAD and wild-type cultures, and IL-1\u03b2 treatment did not affect A\u03b2 levels. Instead, the absence of MT5-MMP significantly reduced A\u03b2 by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1\u03b2 and APP\/A\u03b2, as well as independent control of their levels by MT5-MMP. The lack of MT5-MMP strongly downregulated the AAV-induced neuronal accumulation of the C-terminal APP fragment, C99, and subsequently that of A\u03b2. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1\u03b2 treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Neuroinflammation and hyperexcitability precede A\u03b2 accumulation in developing neural cells with nascent expression of AD transgenes. MT5-MMP deletion is able to tune down basal neuronal inflammation and hyperexcitability, as well as APP\/A\u03b2 metabolism. In addition, MT5-MMP deficiency prevents IL-1\u03b2-mediated effects in brain cells, except hyperexcitability. Overall, this work reinforces the idea that MT5-MMP is at the crossroads of pathogenic AD pathways that are already incipiently activated in developing neural cells, and that targeting MT5-MMP opens interesting therapeutic prospects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-022-02407-z","type":"journal-article","created":{"date-parts":[[2022,3,11]],"date-time":"2022-03-11T02:03:02Z","timestamp":1646964182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["MT5-MMP promotes neuroinflammation, neuronal excitability and A\u03b2 production in primary neuron\/astrocyte cultures from the 5xFAD mouse model of Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"19","author":[{"given":"Dominika","family":"Pilat","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Paumier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Garc\u00eda-Gonz\u00e1lez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Louis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delphine","family":"Stephan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Manrique","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Khrestchatisky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Di Pasquale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K\u00e9vin","family":"Baranger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-2712","authenticated-orcid":false,"given":"Santiago","family":"Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,3,11]]},"reference":[{"issue":"16","key":"2407_CR1","doi-asserted-by":"publisher","first-page":"3167","DOI":"10.1007\/s00018-019-03178-2","volume":"76","author":"S Rivera","year":"2019","unstructured":"Rivera S, Garc\u00eda-Gonz\u00e1lez L, Khrestchatisky M, Baranger K. 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