Novel hydroxytyrosol ester **3b** rescues lifespan and locomotor deficits in *C. elegans* Alzheimer's models.

Alzheimer's disease (AD) is characterized by β-amyloid (Aβ) peptide aggregation and oxidative stress, leading to neuronal dysfunction. Current treatments are largely symptomatic, failing to halt disease progression. Natural polyphenols like oleuropein and hydroxytyrosol show promise with antioxidant and anti-amyloidogenic properties, but oleuropein's limited stability hinders its therapeutic potential. This study addresses the need for more stable and potent analogs to target these interconnected AD pathologies.

Researchers synthesized a series of hydroxytyrosol-based esters, replacing oleuropein's glucoside scaffold with lipophilic substituents. Compounds were screened for interaction with Aβ40 using ESI-MS, circular dichroism (CD), and thioflavin-T (ThT) fluorescence assays, alongside complementary antioxidant assays. The most promising analog, 3b, was then evaluated in vivo in Caenorhabditis elegans models of amyloid-β toxicity. Wild-type nematodes were assessed for toxicity (development, growth, reproduction), while transgenic Aβ42-expressing nematodes were treated with 3b to evaluate lifespan and locomotor deficits.

Most synthesized compounds formed stable non-covalent complexes with Aβ40, inhibiting early aggregation and preventing the peptide's conformational transition from random coil to β-sheet.

Treatment with 3b exhibited no detectable toxicity in wild-type C. elegans, maintaining normal development, growth, and reproductive efficacy. Crucially, 3b rescued lifespan shortening and locomotor deficits in transgenic nematodes expressing human Aβ42 pan-neuronally. This neuroprotective effect was specific, as 3b had no impact on control strains lacking Aβ42 expression. These findings demonstrate that 3b confers functional protection against amyloid-induced toxicity in vivo, combining potent anti-aggregation activity with strong antioxidant properties.