患者源性 tau 和淀粉样蛋白-β 促进体内长期抑郁:肿瘤坏死因子-α 和综合应激反应的作用。

IF 4.1 Q1 CLINICAL NEUROLOGY
Brain communications Pub Date : 2024-09-27 eCollection Date: 2024-01-01 DOI:10.1093/braincomms/fcae333
Neng-Wei Hu, Tomas Ondrejcak, Igor Klyubin, Yin Yang, Dominic M Walsh, Frederick J Livesey, Michael J Rowan
{"title":"患者源性 tau 和淀粉样蛋白-β 促进体内长期抑郁:肿瘤坏死因子-α 和综合应激反应的作用。","authors":"Neng-Wei Hu, Tomas Ondrejcak, Igor Klyubin, Yin Yang, Dominic M Walsh, Frederick J Livesey, Michael J Rowan","doi":"10.1093/braincomms/fcae333","DOIUrl":null,"url":null,"abstract":"<p><p>Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. <i>In vivo</i> electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.</p>","PeriodicalId":93915,"journal":{"name":"Brain communications","volume":null,"pages":null},"PeriodicalIF":4.1000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465085/pdf/","citationCount":"0","resultStr":"{\"title\":\"Patient-derived tau and amyloid-β facilitate long-term depression <i>in vivo</i>: role of tumour necrosis factor-α and the integrated stress response.\",\"authors\":\"Neng-Wei Hu, Tomas Ondrejcak, Igor Klyubin, Yin Yang, Dominic M Walsh, Frederick J Livesey, Michael J Rowan\",\"doi\":\"10.1093/braincomms/fcae333\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. <i>In vivo</i> electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.</p>\",\"PeriodicalId\":93915,\"journal\":{\"name\":\"Brain communications\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.1000,\"publicationDate\":\"2024-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465085/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Brain communications\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1093/braincomms/fcae333\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain communications","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1093/braincomms/fcae333","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

阿尔茨海默病的特征是老年人的认知能力逐渐下降,同时伴有两种致病蛋白淀粉样蛋白-β和tau的沉积。有资料表明,具有突触毒性的可溶性淀粉样蛋白-β聚集体可促进突触长期抑制,这是突触减弱的一种主要形式,与阿尔茨海默氏症患者的认知状况相关。突触毒性 tau 也与阿尔茨海默病患者和其他 tau 病患者的认知能力逐渐下降密切相关,它是否也会导致突触长期抑制仍有待明确。实验采用了年轻的雄性成年大鼠和中年大鼠。突触毒素tau和淀粉样蛋白-β来自不同来源,包括(i)阿尔茨海默病和皮克病tauopathy患者的脑水提取物;(ii)诱导多能干细胞衍生神经元的分泌物,这些神经元来自21号染色体三体综合征患者;以及(iii)合成淀粉样蛋白-β。体内电生理学研究是在氨基甲酸乙酯麻醉的动物体内进行的。在对沙弗侧支-神经通路进行电刺激时,从海马CA1区的放射层记录诱发场兴奋突触后电位。为了研究长期抑制的增强,使用了相对较弱的低频电刺激来触发阈周长期抑制。脑室内注射突触毒素形式的tau或淀粉样蛋白-β。在局部或全身注射后,分别评估了抑制细胞因子肿瘤坏死因子-α或综合应激反应的药物阻止淀粉样蛋白-β或tau对长期抑郁的影响的能力。我们发现,阿尔茨海默病或皮克病患者脑水提取物中的扩散性tau或21号染色体三体综合征的分泌物诱导的多能干细胞衍生神经元,与阿尔茨海默病脑源性淀粉样蛋白-β和合成的低聚淀粉样蛋白-β一样,能有效增强活鼠的突触长期抑制。我们进一步证实,tau 和淀粉样蛋白-β对长期抑制的促进作用与年龄有关,中年动物比青年动物更强。最后,在细胞水平上,我们提供了药理学证据,证明肿瘤坏死因子-α和综合应激反应是突触毒性tau和淀粉样蛋白-β促进长期抑郁的下游介质。总之,这些发现揭示了突触毒性tau和淀粉样蛋白-β对年龄依赖性突触减弱的促进作用。针对tau和淀粉样蛋白-β突触毒性的共同机制(如肿瘤坏死因子-α或综合应激反应)进行药物治疗,为治疗早期阿尔茨海默病提供了一种有吸引力的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Patient-derived tau and amyloid-β facilitate long-term depression in vivo: role of tumour necrosis factor-α and the integrated stress response.

Alzheimer's disease is characterized by a progressive cognitive decline in older individuals accompanied by the deposition of two pathognomonic proteins amyloid-β and tau. It is well documented that synaptotoxic soluble amyloid-β aggregates facilitate synaptic long-term depression, a major form of synaptic weakening that correlates with cognitive status in Alzheimer's disease. Whether synaptotoxic tau, which is also associated strongly with progressive cognitive decline in patients with Alzheimer's disease and other tauopathies, also causes facilitation remains to be clarified. Young male adult and middle-aged rats were employed. Synaptotoxic tau and amyloid-β were obtained from different sources including (i) aqueous brain extracts from patients with Alzheimer's disease and Pick's disease tauopathy; (ii) the secretomes of induced pluripotent stem cell-derived neurons from individuals with trisomy of chromosome 21; and (iii) synthetic amyloid-β. In vivo electrophysiology was performed in urethane anaesthetized animals. Evoked field excitatory postsynaptic potentials were recorded from the stratum radiatum in the CA1 area of the hippocampus with electrical stimulation to the Schaffer collateral-commissural pathway. To study the enhancement of long-term depression, relatively weak low-frequency electrical stimulation was used to trigger peri-threshold long-term depression. Synaptotoxic forms of tau or amyloid-β were administered intracerebroventricularly. The ability of agents that inhibit the cytokine tumour necrosis factor-α or the integrated stress response to prevent the effects of amyloid-β or tau on long-term depression was assessed after local or systemic injection, respectively. We found that diffusible tau from Alzheimer's disease or Pick's disease patients' brain aqueous extracts or the secretomes of trisomy of chromosome 21 induced pluripotent stem cell-derived neurons, like Alzheimer's disease brain-derived amyloid-β and synthetic oligomeric amyloid-β, potently enhanced synaptic long-term depression in live rats. We further demonstrated that long-term depression facilitation by both tau and amyloid-β was age-dependent, being more potent in middle-aged compared with young animals. Finally, at the cellular level, we provide pharmacological evidence that tumour necrosis factor-α and the integrated stress response are downstream mediators of long-term depression facilitation by both synaptotoxic tau and amyloid-β. Overall, these findings reveal the promotion of an age-dependent synaptic weakening by both synaptotoxic tau and amyloid-β. Pharmacologically targeting shared mechanisms of tau and amyloid-β synaptotoxicity, such as tumour necrosis factor-α or the integrated stress response, provides an attractive strategy to treat early Alzheimer's disease.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
CiteScore
7.00
自引率
0.00%
发文量
0
审稿时长
6 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信