De Paolis Maria Luisa, Loffredo Gilda, Krashia Paraskevi, La Barbera Livia, Nobili Annalisa, Cauzzi Emma, Babicola Lucy, Di Segni Matteo, Coccurello Roberto, Puglisi-Allegra Stefano, Latagliata Emanuele Claudio, D'Amelio Marcello
Department of Medicine and Surgery, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy.
Department of Sciences and Technologies for Sustainable Development and One Health, Università Campus Bio-Medico Di Roma, Via Alvaro del Portillo, 21, 00128, Rome, Italy.
Alzheimers Res Ther. 2025 Apr 29;17(1):94. doi: 10.1186/s13195-025-01736-4.
Emerging evidence implicates early dysfunction of dopaminergic neurons in the Ventral Tegmental Area (VTA) as a key contributor to Alzheimer's Disease (AD) pathophysiology. Specifically, the VTA dopaminergic neurodegeneration and the consequent reduction of dopamine (DA) in mesocorticolimbic targets are associated with the onset of cognitive impairments and neuropsychiatric-like manifestations in AD animal models. Moreover, decreased midbrain volume and functional VTA disconnection are identified as predictors of accelerated progression from Mild Cognitive Impairment to AD-dementia in clinical populations. Given these findings, interventions capable of directly modulating VTA activity and augmenting DA release, despite the ongoing neurodegeneration, may hold therapeutic potential for mitigating DA-related deficits in AD. This study aims at evaluating the therapeutic potential of prefrontal transcranial Direct Current Stimulation (tDCS) in the Tg2576 mouse model of AD, exhibiting early VTA dopaminergic neurodegeneration.
Repeated tDCS was applied to assess its ability to activate VTA DA neurons. We also evaluated tDCS effects on synaptic plasticity, cognitive and non-cognitive behaviours and AD-related pathology. Hippocampal DA release and Nucleus Accumbens (NAc) DA transporter (DAT) expression were measured. With immunohistochemistry we examined microglial density and morphological complexity at different disease stages. Additionally, intracellular amyloid-β (Aβ) levels and plaque burden were evaluated to determine the impact of tDCS on AD pathology.
Prefrontal tDCS enhanced the activity of VTA dopaminergic neurons, leading to increased hippocampal DA release and higher DAT levels in the NAc. The enhanced DA outflow is associated with restored CA3-CA1 synaptic plasticity and improvements in recognition memory and motivational behaviours. tDCS reduced microglial numbers and morphological complexity in Tg2576 mice at both pre-plaque stage (7-months) and at an advanced stage characterized by plaque accumulation (12-months). Notably, tDCS also decreased Aβ plaque burden, although no changes in intracellular Aβ levels were observed in younger Tg2576 mice.
These findings highlight the multifaceted therapeutic potential of prefrontal tDCS in targeting key AD pathophysiological hallmarks, including dopaminergic dysfunction, synaptic impairments, neuroinflammation and plaque deposition. As a non-invasive neuromodulatory approach, prefrontal tDCS emerges as a promising early intervention strategy to complement existing AD treatments, with the potential to improve patient outcomes and quality of life.
新出现的证据表明，腹侧被盖区（VTA）多巴胺能神经元的早期功能障碍是阿尔茨海默病（AD）病理生理学的关键促成因素。具体而言，VTA多巴胺能神经变性以及中脑边缘系统靶点中多巴胺（DA）的相应减少与AD动物模型中认知障碍和类神经精神症状的发作有关。此外，中脑体积减小和功能性VTA连接中断被确定为临床人群中从轻度认知障碍加速进展为AD痴呆的预测指标。鉴于这些发现，尽管存在持续的神经变性，但能够直接调节VTA活动并增加DA释放的干预措施可能具有减轻AD中DA相关缺陷的治疗潜力。本研究旨在评估前额叶经颅直流电刺激（tDCS）在表现出早期VTA多巴胺能神经变性的Tg2576 AD小鼠模型中的治疗潜力。
应用重复tDCS来评估其激活VTA DA神经元的能力。我们还评估了tDCS对突触可塑性、认知和非认知行为以及AD相关病理学的影响。测量了海马DA释放和伏隔核（NAc）DA转运体（DAT）表达。通过免疫组织化学检查了不同疾病阶段的小胶质细胞密度和形态复杂性。此外，评估了细胞内淀粉样β（Aβ）水平和斑块负担，以确定tDCS对AD病理学的影响。
前额叶tDCS增强了VTA多巴胺能神经元的活性，导致海马DA释放增加和NAc中DAT水平升高。增强的DA流出与CA3-CA1突触可塑性的恢复以及识别记忆和动机行为的改善有关。在斑块前期（7个月）和以斑块积累为特征的晚期（12个月），tDCS均减少了Tg2576小鼠中的小胶质细胞数量和形态复杂性。值得注意的是，tDCS还降低了Aβ斑块负担，尽管在较年轻的Tg2576小鼠中未观察到细胞内Aβ水平的变化。
这些发现突出了前额叶tDCS在针对关键AD病理生理特征方面的多方面治疗潜力，包括多巴胺能功能障碍、突触损伤、神经炎症和斑块沉积。作为一种非侵入性神经调节方法，前额叶tDCS作为一种有前景的早期干预策略出现，可补充现有的AD治疗方法，有可能改善患者预后和生活质量。
