Gliaudelytė Lina, Rushton Steven P, Berlinguer-Palmini Rolando, Thomas Alan J, Morris Christopher M
Alzheimer's Society Doctoral Training Centre, Edwardson Building, Newcastle University, Newcastle upon Tyne, UK.
School of Natural and Environmental Sciences, Agriculture Building, Newcastle University, Newcastle upon Tyne, UK.
Transl Psychiatry. 2025 Mar 20;15(1):89. doi: 10.1038/s41398-025-03298-3.
In addition to the core clinical features of fluctuating cognition, visual hallucinations, and parkinsonism, individuals with dementia with Lewy bodies (DLB) frequently experience chronic and debilitating major depression. Treatment of depression in DLB is hampered by a lack of available effective therapies and standard serotonergic medication for major depressive disorder (MDD) is typically ineffective. Dysfunction of dopaminergic neurotransmission contributing to anhedonia and loss of motivation has been described in MDD. The subgenual anterior cingulate cortex (sgACC) is important in mood regulation and in the symptomatic expression of depression, displaying structural, functional and metabolic abnormalities in MDD. To assess dopaminergic and serotonergic synaptic changes in DLB, post mortem sgACC tissue from DLB donors with and without depression was investigated using high-resolution stimulated emission depletion (STED) microscopy, as well as Western and dot blotting techniques. STED imaging demonstrated the presence of α-synuclein within individual dopaminergic terminals in the sgACC, α-synuclein presence showing a significant positive correlation with increased synaptosomal associated protein 25 kDa (SNAP25) volumes in depressed DLB cases. A reduction in dopaminergic innervation in the sgACC was observed in DLB cases with depression compared to controls (p < 0.001), but not in non-depressed DLB donors, along with reduced levels of multiple dopaminergic markers and receptors. Limited alterations were observed in serotonergic markers. Our work demonstrates a role for dopaminergic neurotransmission in the aetiology of depression in DLB. Careful and selective targeting of dopaminergic systems in the sgACC may be a therapeutic option for treatment of depression in DLB.
除了认知波动、视幻觉和帕金森症等核心临床特征外，路易体痴呆（DLB）患者还经常经历慢性且使人衰弱的重度抑郁症。DLB抑郁症的治疗因缺乏有效的可用疗法而受阻，用于治疗重度抑郁症（MDD）的标准血清素能药物通常无效。MDD中已描述多巴胺能神经传递功能障碍导致快感缺失和动机丧失。膝下前扣带回皮质（sgACC）在情绪调节和抑郁症的症状表达中很重要，在MDD中表现出结构、功能和代谢异常。为了评估DLB中多巴胺能和血清素能突触变化，使用高分辨率受激发射损耗（STED）显微镜以及蛋白质免疫印迹和斑点印迹技术，对有抑郁症和无抑郁症的DLB供体的死后sgACC组织进行了研究。STED成像显示sgACC中单个多巴胺能终末内存在α-突触核蛋白，在抑郁的DLB病例中，α-突触核蛋白的存在与突触体相关蛋白25 kDa（SNAP25）体积增加呈显著正相关。与对照组相比，患有抑郁症的DLB病例中观察到sgACC中多巴胺能神经支配减少（p < 0.001），但在无抑郁症的DLB供体中未观察到，同时多种多巴胺能标志物和受体水平降低。血清素能标志物的变化有限。我们的研究表明多巴胺能神经传递在DLB抑郁症的病因中起作用。对sgACC中的多巴胺能系统进行谨慎且有选择性的靶向治疗可能是治疗DLB抑郁症的一种选择。
