Polysaccharides targeting organelle network dysfunction in Alzheimer's disease: A review

Alzheimer's disease (AD) is driven by an interrelated pathological network, which to some extent explains the limited efficacy of single-target therapies and constitutes a significant challenge in current clinical treatment. Emerging evidence indicates that dysfunction and crosstalk among mitochondria, the endoplasmic reticulum, and lysosome-autophagy form a core organelle network that amplifies oxidative stress and exacerbates proteostatic imbalance, neuroinflammation, and synaptic failure. In this review, we summarize natural and engineered polysaccharides as potential multitarget modulators that may influence individual organelle-associated pathways involved in AD-related dysfunction. We discuss how the structural parameters of polysaccharides (e.g., molecular weight, monosaccharide composition, glycosidic linkages, branching, and charge density) are associated with bioactivities through receptor-related signaling pathways, redox and inflammatory regulation, proteostasis/autophagy modulation, and, when applicable, potential gut-brain axis involvement. Furthermore, we highlight rational design strategies (e.g., sulfation and carboxymethylation) and formulation/delivery considerations that may increase efficacy and translational readiness. Finally, key challenges, including heterogeneity, mechanism attribution, brain delivery, and standardization, are outlined to guide the development of polysaccharide-based strategies potentially addressing organelle-associated dysfunction in AD.