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.

摘要：背景与目标：阿尔茨海默病行为表现的生物学基础尚不明确。行为失禁，阿尔茨海默病的一种被忽视的表现，可能导致护理者负担沉重，且缺乏有效的管理方法。本研究在先前关于阿尔茨海默病中失禁行为的研究以及通过经颅磁刺激（rTMS）增加脑源性神经营养因子（BDNF）的潜在治疗方法的基础上进行了扩展。方法：对47只3xTg-AD（阿尔茨海默病）和52只B6（野生型）小鼠分别给予ANA12（TrkB受体拮抗剂）或溶剂（盐水）和随后每日进行rTMS或安慰剂治疗。经过14天的治疗和注射后，对小鼠在多种行为认知测试中的行为进行评估。随后对小鼠进行灌注，并对脑样本进行组织学处理和蛋白质分析。对脑匀浆进行分析，以检测BDNF及其下游信号分子。结果：开放场测试表明，3xTg-AD小鼠的总移动距离少于B6小鼠。仅给予ANA12的3xTg-AD-安慰剂小鼠组的移动距离显著少于B6-ANA12-安慰剂或B6-溶剂-安慰剂小鼠组（p<0.05），而无论注射与否，3xTg-AD-rTMS小鼠与任何组别均无显著差异，表明rTMS具有某种校正影响。3xTg-AD小鼠的BDNF和TrkB水平显著高于野生型小鼠。结论：使用rTMS治疗阿尔茨海默病可积极影响行为失禁的某些要素，但并非所有行为异常。rTMS改变了3xTg-AD开放场行为测试的测量结果，消除了未经治疗3xTg-AD与B6基因型之间的显著差异。尽管有益，但仍需进一步研究rTMS作为阿尔茨海默病治疗手段及其生物学基础。