Dendrobium huoshanense stem polysaccharide protects against Alzheimer's disease by modulating SCFAs/GLP-1...

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. The stem of Dendrobium huoshanense is a traditional medicinal food. This study aimed to investigate the effect of cultivated D. huoshanense stem polysaccharide (cDHPS) on AD and elucidate its mechanisms using an Aβ_1-42-induced AD mouse model. Results showed that cDHPS significantly improved the cognitive dysfunction and ameliorated the hippocampal neuronal injury of AD mice. Meanwhile, cDHPS effectively alleviated the neuroinflammation of AD mice not only by decreasing the expression of caspase-1, NOD-like receptor family pyrin domain-containing 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC), as well as their downstream inflammatory cytokines, but also by inhibiting the activation of microglia and astrocytes. Furthermore, the levels of glucagon-like peptide-1 (GLP-1) in the hippocampus, plasma, and intestine of AD mice were markedly elevated by cDHPS, along with an increase in intestinal short-chain fatty acids (SCFAs) levels. However, the treatment of exendin 9-39, a GLP-1 receptor antagonist, weakened the protective effect of cDHPS against AD, and the depletion of SCFAs reversed the beneficial effects of cDHPS on cognitive dysfunction, hippocampal neuronal injury, neuroinflammation, and GLP-1 secretion in AD mice. These results suggest that cDHPS could protect against AD by modulating the SCFAs/GLP-1 axis-mediated neuroinflammation suppression.