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 remains incompletely understood. In this exploratory, proof-of-concept study, we investigated whether taliglucerase alfa (TAL), a recombinant human GCase, may influence 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 low-molecular-weight Aβ 1−42 oligomer-enriched assemblies (oAβ 1−42 ), followed by treatment with TAL. Soluble Aβ levels and selected components of the autophagy–lysosome pathway, including GCase, cathepsin B, p62/sequestosome-1 (p62/SQSTM1), and mammalian target of rapamycin (mTOR), were evaluated using Western blotting, ELISA, and RT-PCR. In this in vitro model, TAL treatment was associated with a reduction in intracellular monomeric Aβ levels. This observation was accompanied by changes in mTOR signaling and p62 levels, suggestive of modulation of autophagy-related processes. Overall, these results provide preliminary, hypothesis-generating evidence supporting a potential association between lysosomal GCase augmentation and Aβ-related and autophagy-associated processes in AD. Further studies, including expanded experimental validation and in vivo investigations, are required to clarify the underlying mechanisms and translational relevance.
Özkurt et al. (Mon,) studied this question.