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&lt;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.摘要：背景/目的：阿尔茨海默病（Alzheimer’s Disease, AD）行为表现的生物学基础迄今尚未阐明。行为脱抑制作为阿尔茨海默病一种易被忽视的临床表现，可给照料者带来沉重负担，且目前尚无有效的干预手段。本研究在既往关于阿尔茨海默病脱抑制行为及采用重复经颅磁刺激（repetitive Transcranial Magnetic Stimulation, rTMS）提升脑源性神经营养因子（Brain-Derived Neurotrophic Factor, BDNF）的潜在治疗方案的研究基础上进行拓展。 方法：本研究共纳入47只3xTg-AD（阿尔茨海默病模型）小鼠与52只B6（野生型）小鼠，分别给予ANA12（酪氨酸激酶受体B（Tropomyosin Receptor Kinase B, TrkB）受体拮抗剂）或赋形剂（生理盐水）处理，随后每日接受rTMS或假刺激（Sham）治疗。经过14天的给药与治疗后，通过多项行为学认知测试评估小鼠的行为表现。随后对小鼠进行灌流取材，对脑组织样本开展组织学检测与蛋白质分析。对脑匀浆进行BDNF及其下游信号分子的检测分析。 结果：旷场实验结果显示，3xTg-AD小鼠的总移动距离显著短于B6野生型小鼠。仅接受ANA12处理的3xTg-AD-假刺激组小鼠，其总移动距离显著低于B6-ANA12-假刺激组与B6-赋形剂-假刺激组（p<0.05）；而所有接受rTMS处理的3xTg-AD小鼠（无论给药类型）的移动距离与其他各组均无显著差异，表明rTMS具有一定的行为矫正作用。3xTg-AD小鼠的BDNF与TrkB表达水平显著高于野生型小鼠。 结论：采用rTMS治疗阿尔茨海默病可对脱抑制相关行为异常产生积极影响，但无法改善所有行为障碍。rTMS可改变3xTg-AD小鼠在旷场实验中的行为指标，消除未处理的3xTg-AD小鼠与B6野生型小鼠间的固有差异，并在两组间产生新的显著差异。尽管rTMS具有上述治疗益处，仍需进一步开展相关研究以明确其用于阿尔茨海默病治疗的潜力及相关生物学机制。