Enhancing cognitive memory function using <i>Phyllanthus emblica</i> polysaccharides <i>via</i> modulating autophagy and reshaping the gut microbiota

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by neuroinflammation, oxidative stress, amyloid-beta (Aβ) plaque buildup, Tau hyperphosphorylation, and gut microbiota imbalance. Natural polysaccharides have been shown to mitigate cognitive decline by regulating the microbiota-gut-brain axis and autophagy, inhibiting neuroinflammation, enhancing Aβ efflux, and facilitating the clearance of Tau protein. <i>Phyllanthus emblica</i> polysaccharides (PEP) exhibit anti-inflammatory, antioxidant, and gut microbiota-modulating properties in colitis and obese mice. However, the potential of PEP in AD prevention remains unclear, prompting the need to investigate the underlying mechanisms of PEP in AD prevention. Physicochemical analysis characterized PEP (MW: 1.182 × 10³ kDa) as a non-crystalline, heat-stable α-acidic pyran heteropolysaccharide composed of galactose and arabinose monosaccharides. <i>In vivo</i> results showed that PEP administration significantly alleviated cognitive decline by reducing neuroinflammatory cytokines (TNF-α, IL-6, and IL-1β) and MDA levels while increasing anti-inflammatory factors (IL-4 and IL-10) and antioxidants (SOD, catalase, and GPx) in AlCl₃-treated rats. Mechanistically, PEP upregulated autophagy-related proteins (Atg5, Beclin1, and LC3B) and LRP1 expression while downregulating AD-related proteins (BACE1, APP, Aβ, and phospho-Tau^Ser404). Additionally, PEP treatment elevated short-chain fatty acids (SCFAs) and SCFA-producing bacteria, particularly the <i>Christensenellaceae_R-7_group</i>. In summary, PEP demonstrated preventive effects by exerting antioxidant, anti-inflammatory, autophagy-inducing, AD-related protein-suppressing, and microbiota-modulating properties, alleviating cognitive impairment in rats subjected to AlCl₃ treatment.