VIRAL-MEDIATED MODULATION OF MT5-MMP AS A POTENTIAL THERAPEUTIC APPROACH IN TRANSGENIC AND CELLULAR MODELS OF ALZHEIMER’S DISEASE

Membrane-type 5 matrix metalloproteinase (MT5-MMP) contributes to amyloidogenesis by cleaving the amyloid precursor protein (APP), increasing toxic C99 and Aβ production. MT5-MMP knock-out reduces Alzheimer’s disease (AD) neuropathology, while preserving cognition and long-term potentiation in 5xFAD mice. Notably, mutations in selected domains of the proteinase reduce C99 and Aβ levels in heterologous cell systems.
Aims: We investigate how AAV-encoded mutant MT5-MMP forms (AAV-MT5) influence early AD pathology in 5xFAD mice and in human iPS-derived neurons.
Methods: 5xFAD mice were injected intracerebroventricularly with AAV-MT5 variants and a PolyA control at postnatal day 1. Four months later, their cognitive performance was tested using behavioural tests. Immunostainings assessed amyloid plaques, intracellular Aβ, and glial activation. Levels of Aβ peptides, C99 and neuroinflammatory markers were also measured using Western blots and MSD assays. In addition, HA-C99 and AAV-MT5 variants are being transduced in human iPS-derived neurons to evaluate the impact of the latter on C99 content and subcellular localisation using Western blots, immunocytochemistry and microscopy.
Results: Full-length MT5-MMP expression exacerbates amyloid pathology and neuroinflammation, while promoting anxiety-like behaviour and hyperactivity in 5xFAD mice. However, specific AAV-MT5 variants appear to decrease amyloid pathology and neuroinflammation. We expect specific variants to also influence working memory. In our cellular model, we anticipate changes in C99 levels and localisation depending on the AAV-MT5 variant.
Conclusions: Our study should provide new evidence for the role of specific domains of MT5-MMP in APP metabolism and help validate MT5-MMP as a potential therapeutic target to guide new AD treatments.