Polysaccharides from Ganoderma lucidum attenuate cognitive impairment in 5xFAD mice by inhibiting oxidative stress and modulating mitochondrial dynamics via the Nrf2/antioxidative axis activation.

Oxidative stress and mitochondrial dynamics imbalance are key contributors to AD pathogenesis. GLPS, an extract from Ganoderma lucidum spores, exhibits anti-inflammatory, antioxidant, and immunomodulatory properties. However, the roles of GLPS in regulating oxidative stress and mitochondrial dynamics in AD remain poorly understood. Here, the underlying mechanisms of neuroprotective effects on cognitive dysfunction in 5 × FAD mice were explored. C57BL/6 mice served as WT controls, while 5 × FAD mice were divided into an AD group and an AD + GLPS group. The mice in AD + GLPS group were administered daily GLPS (25 mg/kg) by i.p. injection for two months, while WT and AD mice received an equivalent volume of normal saline. The results indicated that GLPS markedly improved cognitive function and decreased p-tau and Aβ levels in 5 × FAD mice. Moreover, GLPS alleviated oxidative stress by increasing SOD levels and decreasing MDA concentrations. It also inhibited excessive mitochondrial fragmentation by decreasing the expression of p-Drp1 and Fis1, while increasing the levels of Mfn1, Mfn2, and OPA1 in 5 × FAD mice. Mechanistically, GLPS activated Nrf2, leading to a marked upregulation of antioxidant enzymes, including HO- 1, NQO1, and SOD2 in 5 × FAD mice. Collectively, these findings suggest that GLPS ameliorates cognitive deficits in 5 × FAD mice by reducing oxidative stress and modulating mitochondrial dynamics through Nrf2-mediated antioxidant enzyme activation.