Bushen Huoxue Acupuncture alleviates alzheimer's disease progression via the E3 ubiquitin ligase SMURF2‑mediated ubiquitination of LAPTM5.

This study investigated the therapeutic potential and mechanism of Bushen Huoxue Acupuncture (BSHXA) against Alzheimer's disease (AD) using integrated in vivo and in vitro approaches. In eight-month-old SAMP8 mice, BSHXA treatment significantly improved cognitive performance, alleviated hippocampal neuronal damage and neuroinflammation, and downregulated LAPTM5 expression. Complementary in vitro experiments in lipopolysaccharide (LPS)-stimulated BV2 microglia demonstrated that LAPTM5 knockdown reduced apoptosis, pathological protein accumulation, and pro-inflammatory M1 polarization. Through bioinformatic prediction and Co-IP assays, SMURF2 was identified as an E3 ubiquitin ligase directly interacting with LAPTM5 and promoting its ubiquitin-dependent degradation. SMURF2 overexpression in vitro reproduced protective effects similar to LAPTM5 knockdown. Importantly, in vivo knockdown of SMURF2 abolished the therapeutic benefits of BSHXA. Collectively, these findings demonstrate that BSHXA ameliorates AD progression by upregulating SMURF2, which promotes the ubiquitination and subsequent degradation of LAPTM5, thereby suppressing microglial M1 polarization, inhibiting neuroinflammatory responses, and attenuating AD pathologies. The SMURF2-LAPTM5 axis is established as a key mechanistic pathway underlying the neuroprotective effects of BSHXA.