Cremastra appendiculata Polysaccharides Alleviate Neurodegenerative Diseases in Caenorhabditis elegans: Targeting Amyloid-β Toxicity, Tau Toxicity and Oxidative Stress

Alzheimer's disease (AD) is characterized by oxidative stress, amyloid-beta (Aβ) deposition, and tau hyperphosphorylation. While polysaccharides have demonstrated anti-AD effects, the properties of <i>Cremastra appendiculata</i> polysaccharides (CAPs) remain underexplored. This study evaluates the physicochemical properties, antioxidant activity, anti-AD effects, and underlying mechanisms of CAP in vitro and in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) AD models. CAP, containing 22.37% uronic acid, is stable below 270 °C and adopts a triple helix structure. Scanning electron microscopy (SEM) reveals an irregular layered architecture. In vitro, CAP exhibits significant antioxidant activity, protecting PC12 cells from Aβ-induced cytotoxicity. In <i>C. elegans</i>, CAP extends the lifespan in a concentration-dependent manner without affecting growth, alleviating tau-induced locomotor defects, reducing Aβ-induced paralysis and serotonin hypersensitivity, and decreasing Aβ deposition by 79.96% at 2.0 mg/mL. CAP enhances antioxidant capacity and heat resistance by reducing reactive oxygen species (ROS) levels and increasing glutathione S-transferase 4 (GST-4) and glutathione peroxidase (GSH-Px) activities. Additionally, CAP upregulates key genes in the insulin/insulin-like growth factor signaling pathway, including <i>daf-16</i> and <i>skn-1</i>, along with their downstream targets (<i>sod-3</i>, <i>ctl-1</i>, <i>gst-4</i>, <i>hsp-70</i>). These findings suggest that CAP has potent antioxidant and anti-AD effects, alleviating Aβ- and tau-induced toxicity, and may serve as a promising therapeutic agent for Alzheimer's disease.