Tanaka Makoto T, Miki Yasuo, Mori Fumiaki, Kon Tomoya, Furukawa Tomonori, Shimoyama Shuji, Tatara Yota, Ozaki Taku, Bettencourt Conceição, Warner Thomas T, Wakabayashi Koichi
Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan.
Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London WC1N 1PJ, UK.
Brain Commun. 2024 Aug 20;6(4):fcae193. doi: 10.1093/braincomms/fcae193. eCollection 2024.
Abnormal α-synuclein (αSyn), including an oligomeric form of αSyn, accumulates and causes neuronal dysfunction in the brains of patients with multiple system atrophy. Neuroprotective drugs that target abnormal αSyn aggregation have not been developed for the treatment of multiple system atrophy. In addition, treating diseases at an early stage is crucial to halting the progress of neuronal damage in neurodegeneration. In this study, using early-stage multiple system atrophy mouse model and kinetic analysis, we investigated how intranasal and oral administration of trehalose can improve multiple system atrophy pathology and clinical symptoms. The multiple system atrophy model showed memory impairment at least four weeks after αSyn induction. Behavioural and physiological analyses showed that intranasal and oral administration of trehalose reversed memory impairments to near-normal levels. Notably, trehalose treatment reduced the amount of toxic αSyn and increased the aggregated form of αSyn in the multiple system atrophy model brain. kinetic analysis confirmed that trehalose accelerated the aggregate formation of αSyn. Based on our findings, we propose a novel strategy whereby accelerated αSyn aggregate formation leads to reduced exposure to toxic αSyn oligomers, particularly during the early phase of disease progression.
异常的α-突触核蛋白（αSyn），包括αSyn的寡聚体形式，在多系统萎缩患者的大脑中积累并导致神经元功能障碍。尚未开发出针对异常αSyn聚集的神经保护药物来治疗多系统萎缩。此外，在疾病早期进行治疗对于阻止神经退行性变中神经元损伤的进展至关重要。在本研究中，我们使用早期多系统萎缩小鼠模型和动力学分析，研究了经鼻和口服海藻糖如何改善多系统萎缩的病理和临床症状。多系统萎缩模型在αSyn诱导后至少四周出现记忆障碍。行为和生理分析表明，经鼻和口服海藻糖可将记忆障碍逆转至接近正常水平。值得注意的是，海藻糖治疗减少了多系统萎缩模型大脑中有毒αSyn的数量，并增加了αSyn的聚集形式。动力学分析证实海藻糖加速了αSyn的聚集形成。基于我们的发现，我们提出了一种新策略，即加速αSyn聚集形成可减少有毒αSyn寡聚体的暴露，尤其是在疾病进展的早期阶段。
