rTMS Modulation of Behavioral and Biological Measures in 3xTg-AD Mice

Abstract: Background/Objectives: The biological basis for behavioral manifestations of Alz-heimer’s disease remains unclear. Behavioral disinhibition, an overlooked manifestation of Alz-heimer’s disease, can result in substantial caregiver burden, and lacks effective management. This study expands upon previous work investigating disinhibited behavior in Alzheimer’s disease and a potential treatment of increasing brain-derived neurotrophic factor (BDNF) with rTMS. Methods: 47 3xTg-AD (Alzheimer’s) and 52 B6 (wildtype) mice were administered with ANA12 (an antagonist of TrkB receptor) or Vehicle (saline) and then rTMS or Sham treatment daily. After 14 days of treatments and injections, mouse behavior was assessed under various behavioral cognitive tests. Mice were then perfused, and brain samples were processed for histology and protein assays. Brain homogenates were analyzed for BDNF and its downstream signaling mol-ecules. Results: Open field testing demonstrated that 3xTg-AD mice traveled less total distance than B6 mice. 3xTg-AD-Sham mice injected with ANA12 were the only group to travel signifi-cantly less distance than B6-ANA12-Sham or B6-Vehicle-Sham mice (p<0.05), while 3xTg-AD-rTMS mice (irrespective of injection) were not significantly different from any group, indicating some corrective influence from rTMS. 3xTg-AD mice had significantly greater meas-ured levels of BDNF and TrkB than the wild type mice. Conclusions: Treatment of Alzheimer’s disease using rTMS positively affects elements of disinhibition, but not all behavioral abnormali-ties. rTMS shifts 3xTg-AD open field behavioral test measures, eliminating and generating sig-nificant differences between untreated 3xTg-AD and B6 genotypes. Despite its benefit, further in-vestigation of rTMS as a treatment for Alzheimer’s disease as well as its biological underpin-nings are needed.