Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation.
Tuberous sclerosis complex is a novel, amyloid-independent tauopathy associated with elevated phosphorylated 3R/4R tau aggregation.
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DOI：
10.1186/s40478-022-01330-x
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发表时间：
2022-03-03
影响因子：
7.1
通讯作者：
Wang SJ
中科院分区：
文献类型：
--
作者：
Liu AJ;Lusk JB;Ervin J;Burke J;O'Brien R;Wang SJ
多发性硬化症（TSC）是由TSC 1和TSC 2基因突变引起的常染色体显性遗传的神经发育障碍。这些突变引起哺乳动物雷帕霉素靶蛋白（mTOR）通路的过度激活，导致累及各种器官系统的非恶性肿块的发展。TSC患者也会出现神经精神症状，统称为脑硬化综合征相关神经精神障碍（TAND）。由于TSC的研究进展，患者现在可以活到50岁以上。许多人在40多岁时开始经历记忆和执行功能的客观损害，并得到正式神经心理学测试的支持。生物标志物分析已经描述了TAND患者脑脊液中磷酸化tau-181水平升高。Tau-PET成像还显示放射性示踪剂flortaucipir（AV 1451）的局灶性蓄积，表明TSC可能是由磷酸化tau蓄积引起的神经退行性疾病。然而，据报道，flortaucipir示踪剂具有显著的脱靶结合，从而无法得出关于TSC中神经变性的分子病因学的明确结论。因此，我们启动了成人脑组织中AV1451和磷酸化Tau的共定位（CAPA）研究。本研究旨在确定flortaucipir是否与TSC患者脑中的磷酸化tau结合，并进一步确定TSC中观察到的特异性tau亚型。我们的研究结果表明，flortaucipir标记磷酸化tau的3R/4R亚型，这在阿尔茨海默病中常见。然而，淀粉样蛋白染色是阴性的，在成人TSC患者的大脑。因此，我们得出结论，TAND症状是由于在阿尔茨海默病中看到的磷酸化tau亚型的积累。这项研究表明，哺乳动物雷帕霉素靶蛋白途径的超活化可能在3R/4R tau聚集的淀粉样蛋白非依赖性发展中发挥作用。我们的发现可能会导致一个用于治疗这两种疾病的抗tau疗法的新时代。
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by mutations in the TSC1 and TSC2 genes and autosomal dominantly inherited. These mutations cause hyperactivation of the mammalian Target of Rapamycin (mTOR) pathway, leading to the development of nonmalignant masses involving various organ systems. Patients with TSC also experience neuropsychiatric symptoms collectively termed Tuberous Sclerosis Complex Associated Neuropsychiatric Disorder (TAND). Due to research advancements in TSC, patients now live well beyond the age of 50. Many experience objective impairment of memory and executive function, supported by formal neuropsychological testing, beginning in their late 40s. Biomarker analysis has described elevated levels of phosphorylated tau-181 in the cerebrospinal fluid of patients with TAND. Tau-PET imaging has also shown focal accumulation of the radiotracer flortaucipir (AV1451), suggesting that TSC may be a neurodegenerative disorder arising from accumulation of phosphorylated tau. However, the flortaucipir tracer has been reported to have significant off-target binding, preventing definitive conclusions from being drawn about the molecular etiology of neurodegeneration in TSC. Therefore, we initiated the Colocalization of AV1451 and Phosphorylated Tau in Adult brain tissue (CAPA) study. This study aimed to determine if flortaucipir is bound to phosphorylated tau in brains of patients with TSC and further sought to determine the specific tau isoform seen in TSC. Our results show that flortaucipir labels the 3R/4R isoform of phosphorylated tau, commonly seen in Alzheimer’s disease. However, amyloid staining was negative in brains of adult patients with TSC. Therefore, we conclude that TAND symptoms are due to the accumulation of the phosphorylated tau isoform seen in Alzheimer’s disease. This study suggests that hyperactivation of the mammalian Target of Rapamycin pathway may play a role in the amyloid-independent development of 3R/4R tau aggregation. Our findings could lead to a new era of anti-tau therapies used to treat both disorders.
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结节性硬化症复杂诊断标准更新：2012年iinternation Tuberous硬化症复杂共识会议的建议。
影响因子：
3.8
作者：
Northrup H;Krueger DA;International Tuberous Sclerosis Complex Consensus Group
通讯作者：
International Tuberous Sclerosis Complex Consensus Group
影响因子：
11.1
作者：
Mattsson N;Schöll M;Strandberg O;Smith R;Palmqvist S;Insel PS;Hägerström D;Ohlsson T;Zetterberg H;Jögi J;Blennow K;Hansson O
通讯作者：
Hansson O
影响因子：
29
作者：
Liu, Andy J.;Staffaroni, Adam M.;Kao, Aimee W.
通讯作者：
Kao, Aimee W.
影响因子：
3.2
作者：
Cai Z;Chen G;He W;Xiao M;Yan LJ
通讯作者：
Yan LJ
影响因子：
3.4
作者：
Jansen, Anna C.;Belousova, Elena;Trollmann, Regina
通讯作者：
Trollmann, Regina