Sarmentoside B removes oligomerized amyloid peptide from neurons by inhibiting `mTOR` and restoring lysosomal function in an in vitro **Alzheimer's disease** model

Alzheimer's disease (AD) is characterized by beta-amyloid (Aβ) plaque deposition, which impairs cellular processes like autophagy. Current therapies often fall short due to the multifactorial nature of AD, necessitating new approaches targeting alternative molecular pathways. Dysfunctional autophagy and lysosomal impairment are key contributors to Aβ accumulation and neurodegeneration. Modulating these pathways, particularly through targets like mTOR, offers a promising strategy to clear toxic Aβ aggregates and restore neuronal health. This study explores a novel compound's impact on these critical processes.

Evaluated a molecule (EC5) from the hydrozoan Eudendrium carneum for neuroprotective effects in SH-SY5Y cells exposed to oAβ42. Secretion was fractionated by RP-HPLC. Neuroprotection was assessed via LDH and MTT assays. The purified molecule, EC5, characterized by mass spectrometry, was evaluated for in silico toxicity and calcium dynamics. Lysosomal morphology was assessed using LysoTracker, and cathepsin D activity was determined. Expression of autophagy-related proteins (mTOR, LAMP-1, LC3B) was evaluated by dot blotting, and amyloid plaque clearance was quantified using Thioflavin-T staining.

The steroid glycoside putatively identified as Sarmentoside B (EC5) exhibited significant neuroprotective effects against oAβ42-induced toxicity. It demonstrated no toxicity or alterations in neuronal calcium or sodium channel dynamics. Molecular docking analysis supported an interaction where EC5 reduced mTOR expression. This inhibition of mTOR was linked to restored lysosomal function.

Sarmentoside B restored lysosomal morphology and cathepsin D activity, effectively reversing the impairment induced by oAβ42. This lysosomal restoration promoted the clearance of oAβ42 aggregates, as evidenced by Thioflavin-T staining, leading to reduced neuronal death. The study highlights a direct link between mTOR inhibition, restored lysosomal function, and the removal of toxic amyloid aggregates.