Taliglucerase Alfa Modulates Aβ Load and Autophagy-Related Pathways in Mouse Hippocampal Neurons Exposed to oAβ1-42

Abstract Intraneuronal amyloid-beta (Aβ) accumulation and autophagic dysfunction are key pathological features of Alzheimer's disease (AD). Mutations in GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase (GCase), are linked to several neurodegenerative disorders, but the role of GCase in AD is underexplored. We hypothesized that taliglucerase alfa (TAL), a recombinant human GCase, could reduce intracellular Aβ accumulation by modulating autophagy pathways in a neuronal AD model. Endogenous Aβ accumulation was induced in mouse hippocampal neuronal cells (HT-22) by exposure to an oligomeric Aβ fragment (oAβ₁−₄₂), followed by treatment with TAL. Using Western blotting, ELISA, and RT-PCR, we evaluated soluble Aβ levels and key proteins in the autophagy-lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and the mammalian target of rapamycin (mTOR). In this in vitro model, TAL significantly reduced the intracellular load of monomeric Aβ. This reduction was associated with a restoration of autophagic function, marked by the normalization of mTOR signaling and p62 levels, alongside enhanced lysosomal proteolytic capacity. These findings suggest that enhancing lysosomal GCase levels through enzyme replacement therapy represents a promising therapeutic strategy for the treatment of AD.