| First Author | Pilat D | Year | 2024 |
| Journal | Biomolecules | Volume | 14 |
| Issue | 12 | PubMed ID | 39766352 |
| Mgi Jnum | J:361217 | Mgi Id | MGI:7850953 |
| Doi | 10.3390/biom14121645 | Citation | Pilat D, et al. (2024) Suppression of MT5-MMP Reveals Early Modulation of Alzheimer's Pathogenic Events in Primary Neuronal Cultures of 5xFAD Mice. Biomolecules 14(12) |
| abstractText | We previously reported that membrane-type 5-matrix metalloproteinase (MT5-MMP) deficiency not only reduces pathological hallmarks of Alzheimer's disease (AD) in 5xFAD (Tg) mice in vivo but also impairs interleukin-1 beta (IL-1beta)-mediated neuroinflammation and Abeta 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 21-24 days in vitro (DIV), during which time neurons are organized into a functional mature network. Using wild-type (WT), MT5-MMP(-/-) (MT5(-/-)), 5xFAD (Tg), and 5xFADxMT5-MMP(-/-) (TgMT5(-/-)) mice, we generated primary neuronal cultures that were exposed to IL-1beta 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-1beta-mediated induction of inflammatory genes in TgMT5(-/-) cells compared to Tg cells. Furthermore, the reduced density of dendritic spines in Tg neurons was also prevented in TgMT5(-/-) neurons. IL-1beta caused a strong decrease in the dendritic spine density of WT neurons, which was prevented in MT5(-/-) 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(-/-) neurons, but not in TgMT5(-/-) neurons, and IL-1beta increased this parameter only in Tg neurons. In terms of induced somatic excitability, Tg and TgMT5(-/-) neurons exhibited lower excitability than WT and MT5(-/-), while IL-1beta 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(-/-) neurons after IL-1beta. MT5-MMP deficiency decreased endogenous and overexpressed C83 and C99 levels but did not affect Abeta levels. C99 appears to be cleared by several pathways, including gamma-secretase, the autophagolysosomal system, and also alpha-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. |
