40-Hz transauricular vagal nerve stimulation rescues cognition of 9-month-old APP/PS1 mice via inhibiting hippocampal P2X7 receptor signaling

The lack of any viable therapy for Alzheimer’s disease (AD) evoked the study and utilization of neuromodulation. 40-Hz transauricular vagal nerve stimulation (taVNS) preliminarily showed effectiveness in mice with partial cognitive impairment in our previous work, yet 3 major problems remained unresolved. (1) Can 40-Hz taVNS rescue the cognition of mice exhibiting total cognitive impairment? (2) Are the cognition-rescuing effects of taVNS specific to 40 Hz stimulation? (3) Via P2X7R signaling? Thus, 3 parts were divided to address the above issues in this work using 9-month-old wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice. Behavioral examinations for cognition; western blotting (WB), enzyme-linked immunosorbent assays (ELISA) for Aβ load; WB and ELISA for the P2X7R signaling pathway; Nissl staining for neuroprotective effects were employed. 3 findings can be derived. (1) 40-Hz taVNS rescues cognition of the APP/PS1 mice aged 9 months (but is not effective in WT mice of the same age). (2) The cognition-rescuing effects of taVNS in APP/PS1 mice are frequency-specific, which is 40 Hz in this work (neither 8-Hz taVNS nor 80-Hz taVNS works). (3) The hippocampal P2X7R signaling is a critical mediator of the observed effects (inhibiting P2X7R had similar effects to 40-Hz taVNS, which counteracted activating P2X7R). Therefore, 40-Hz taVNS shows potential as a viable therapy option for AD, with the P2X7R being a prominent target.