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MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease

Abstract : Background: Membrane-type matrix metalloproteinase 5 (MT5-MMP) deficiency in the 5xFAD mouse model of Alzheimer's disease (AD) reduces brain neuroinflammation and amyloidosis, and prevents deficits in synaptic activity and cognition in prodromal stages of the disease. In addition, MT5-MMP deficiency prevents interleukin-1 beta (IL-1β)mediated inflammation in the peripheral nervous system. In this context, we hypothesized that the MT5-MMP/IL-1β tandem could regulate nascent AD pathogenic events in developing neural cells shortly after the onset of transgene activation. Methods: To test this hypothesis, we used 11-14 day in vitro primary cortical cultures from wild type, MT5-MMP −/− , 5xFAD and 5xFAD/MT5-MMP −/− mice, and evaluated the impact of MT5-MMP deficiency and IL-1β treatment for 24 h, by performing whole cell patch-clamp recordings, RT-qPCR, western blot, gel zymography, ELISA, immunocytochemistry and adeno-associated virus (AAV)-mediated transduction. Results: 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-1β, as well as decreased stability of recombinant IL-1β. The levels of amyloid beta peptide (Aβ) were similar in 5xFAD and wild-type cultures, and IL-1β treatment did not affect Aβ levels. Instead, the absence of MT5-MMP significantly reduced Aβ by more than 40% while sparing APP metabolism, suggesting altogether no functional crosstalk between IL-1β and APP/Aβ, 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 Aβ. Finally, MT5-MMP deficiency prevented basal hyperexcitability observed in 5xFAD neurons, but not hyperexcitability induced by IL-1β treatment.
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https://hal.archives-ouvertes.fr/hal-03570912
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Submitted on : Sunday, February 13, 2022 - 6:23:24 PM
Last modification on : Sunday, June 26, 2022 - 3:54:20 AM
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Dominika Pilat, Jean-Michel Paumier, Laura García-González, Laurence Louis, Delphine Stephan, et al.. MT5-MMP promotes neuroinflammation, neuronal excitability and Aβ production in primary neuron/astrocyte cultures from the 5xFAD mouse model of Alzheimer's disease. Journal of Neuroinflammation, BioMed Central, inPress, ⟨10.1186/s12974-022-02407-z⟩. ⟨hal-03570912⟩

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