Transauricular Vagus Nerve Stimulation Attenuates Hippocampal SRPX2 Expression and Reactive Astrocytosis in an Acrolein-Induced Alzheimer’s-Like Rat Model

Abstract

Introduction Acrolein, a highly reactive aldehyde generated during lipid peroxidation, is elevated in Alzheimer’s disease (AD) and has been shown to induce AD-like synaptic and cognitive deficits in experimental models. Transcutaneous auricular vagus nerve stimulation (taVNS) is a noninvasive neuromodulatory intervention with potential cognitive and anti-inflammatory effects. Sushi repeat-containing protein X-linked 2 (SRPX2) is a neuronal complement inhibitor that contributes to synaptic protection by limiting complement mediated synapse elimination. However, the regulation of SRPX2 in acrolein-induced AD-like pathology and its modulation by taVNS remain unclear. This study investigated the effects of taVNS on hippocampal SRPX2 expression and reactive astrocytosis in an acrolein-induced AD-like rat model. Methods Twenty-eight Wistar rats were randomly assigned to an acrolein-exposed cohort (n = 21) or a non-exposed control group (n = 7). Acrolein-exposed rats were further divided into three groups: acrolein-only, sham stimulation of the greater auricular nerve, and vagus nerve stimulation (VNS) of the auricular branch (n = 7 per group). Acrolein was administered by oral gavage at 2.5 mg/kg/day for eight weeks. Sham stimulation and taVNS were subsequently administered for four weeks at 25 Hz, 0.8 mA, and one hour/day. Hippocampal SRPX2 gene expression was quantified using real-time PCR, while reactive astrocytosis was evaluated using glial fibrillary acidic protein (GFAP) immunohistochemistry. Results Acrolein exposure significantly increased hippocampal SRPX2 expression and GFAP-defined reactive astrocytosis compared with non-exposed controls. taVNS significantly reduced SRPX2 expression toward control levels (mean ± SD: 0.48 ± 0.17; p = 0.0075). In addition, taVNS reduced the density of GFAP-positive astrocytes and decreased GFAP staining intensity compared with the acrolein-only condition. Conclusions taVNS attenuated acrolein-induced AD-like hippocampal pathology, as evidenced by reduced SRPX2 expression and reactive astrocytosis. These findings suggest that taVNS may have therapeutic potential as a noninvasive neuromodulatory intervention targeting complement-related neuron-glia mechanisms in sporadic AD. Further studies are warranted to clarify the mechanistic relationship between SRPX2, complement signaling, astrocytic activation, and the neuroprotective effects of taVNS.