Electroacupuncture Prevents Against AD-Like Phenotypes in APP/PS1 Mice: Investigation of the Mechanisms From Cerebral Microangiopathy.

BACKGROUND: Electroacupuncture (EA) has been widely used in Alzheimer's disease (AD) treatment. However, its underlying mechanisms remain poorly elucidated. PURPOSE: This study aimed to investigate the effects of EA on AD-like phenotypes and explore the mechanisms. METHODS: We first evaluated AD-like behaviors and cerebral blood flow (CBF) changes in APPswe/PS1dE9 (APP/PS1) mice at different ages. Subsequently, the therapeutic effects of EA at acupoints Baihui (GV20), Guanyuan (CV4), and Zusanli (ST36), as well as sunitinib, a PDGFRβ-specific inhibitor, on AD-like phenotypes in APP/PS1 mice were investigated. CBF was monitored by laser speckle imaging, and hippocampal synaptic ultrastructure and microvascular morphology were examined by transmission electron microscopy (TEM). Western blot was performed to measure related protein expression. Finally, functional ultrasound (fUS) imaging was used to assess changes in brain-wide functional connectivity. RESULTS: Compared with age-matched wild-type (WT) mice, 6- and 9-month-old APP/PS1 mice exhibited significant cognitive decline, while all age groups (3-, 6-, and 9-month-old) of APP/PS1 mice showed significantly reduced CBF. APP/PS1 mice showed elevated expression of microvascular markers in both the hippocampus and cortex. EA significantly ameliorated AD-like behaviors and prevented CBF reduction as well as microvascular deformation in 6-month-old APP/PS1 mice compared with non-treatment group. TEM and western blot analysis revealed damaged synaptic structure and reduced synaptic proteins in APP/PS1 mice, all of which were markedly alleviated by EA treatment. In addition, EA treatment downregulated the aberrantly elevated expression of PDGFRβ and CD31, enhanced the levels of tight junction proteins (Occludin, Claudin-5, and ZO-1) and glucose transporter 1 (GLUT1), and suppressed the expression of inflammatory proteins. Of note, intervention with sunitinib also improved AD-like behaviors in APP/PS1 mice. Remarkably, fUS imaging results showed that EA enhanced the functional connection between hippocampal regions of APP/PS1 mice. CONCLUSION: Our data demonstrates that EA ameliorates AD-like phenotypes, potentially through preventing microangiopathy.