Suanzaoren Decoction inhibits neuroinflammation and alleviates hippocampal neuronal injury in APP/PS1 transgenic mice by regulating the Hippo-YAP pathway

To investigate the mechanism by which Suanzaoren Decoction (SZRD) ameliorates hippocampal neuronal injury in APP/PS1 mice.

Thirty 7-month-old APP/PS1 transgenic mice were randomized into 3 groups for daily gavage with saline or SZRD at 12.96 or 25.92 g/kg (n=10) for 28 consecutive days, with 10 saline-treated age-matched male C57BL/6J mice as the blank control group. Spatial learning and memory abilities of the mice were evaluated using Morris water maze test. Neuronal integrity and amyloid β (Aβ) deposition were examined with Nissl staining and Thioflavin S staining, respectively, and hippocampal IBA1 expression was detected by immunohistochemistry. IBA1/Aβ immunofluorescence double staining was used to evaluate the spatial relationship between hippocampal microglia and Aβ plaques. RNA sequencing was employed to identify the key targets. Western blotting was performed to detect hippocampal expressions of nuclear factor kappa-B (NF-κB p65), p-NF-κB p65-ser536, interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α), and the Hippo-YAP pathway proteins including mammalian sterile 20-like kinase 1 (MST1), large tumor suppressor 1 (LATS1), Yes-associated protein (YAP1), and p-YAP1-s127.

In APP/PS1 mice, SZRD at both the low and high doses significantly improved learning and memory performance and neuronal organization, increased hippocampal neuronal number, and reduced amyloid-β (Aβ) deposition and IBA1 expression. The treatments also significantly decreased IBA1-positive area, Aβ -positive area, and IBA1/Aβ co-localization in the transgenic mice. RNA sequencing revealed that SZRD downregulated the key genes in the Hippo signaling pathway and inflammation-related genes in APP/PS1 mice. Western blotting demonstrated that SZRS treatment significantly lowered hippocampal expressions of MST1, LATS1, p-YAP1-s127/YAP1, p-NF-κB p65-Ser536/NF-κB p65, IL-1β, IL-6, and TNF-α in APP/PS1 mice.

SZRD ameliorates hippocampal neuronal injury in APP/PS1 mice by regulating the Hippo-YAP signaling pathway and inhibiting neuroinflammation.