创伤性脑损伤导致的病理性 tau 多态性会诱导野生型小鼠产生不同的传播模式和神经炎症反应。

IF 6.7 2区 医学 Q1 NEUROSCIENCES Progress in Neurobiology Pub Date : 2023-12-21 DOI:10.1016/j.pneurobio.2023.102562
Nicha Puangmalai , Nemil Bhatt , Alice Bittar , Cynthia Jerez , Nikita Shchankin , Rakez Kayed
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引用次数: 0

摘要

tau 蛋白的错误折叠和聚集成神经纤维缠结是 tau 病的主要特征。创伤性脑损伤(TBI)已成为诱发tau病发病和进展的潜在风险因素。我们之前的研究发现,单次轻度创伤性脑损伤和重复性轻度创伤性脑损伤导致的可溶性 tau 低聚物存在不同的多态性。然而,协调创伤性脑损伤脑源性 tau 多聚物(TBI-BDTPs)传播的机制仍不明确。在本研究中,我们探讨了TBI-BDTPs是否会启动病理性tau形成,从而导致不同的致病轨迹。野生型小鼠暴露于假性、单次爆炸(SB)或重复爆炸(RB)条件下的TBI-BDTPs,并在注射后2个月和8个月通过行为测定评估其记忆功能。我们的研究结果表明,RB-BDTPs会诱发认知和运动障碍,同时会在注射的海马中产生有毒的tau聚集体。令人震惊的是,这种tau病理变化扩散到皮层,并随着时间的推移而加剧。重要的是,暴露于 RB-BDTP 的动物显示出神经胶质细胞活化加剧、NLRP3 炎性体形成和 TBI 生物标志物增加,尤其是引发了 S100B 的聚集,而 S100B 是神经炎症反应的标志。总之,我们的研究结果揭示了 TBI-BDTP 诱导的 tau 病理学的复杂机制及其与神经炎症过程的关联。这项研究加深了我们对脑外伤后 tau 病及其与神经退行性病变和炎症途径的相互作用的理解。
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Traumatic brain injury derived pathological tau polymorphs induce the distinct propagation pattern and neuroinflammatory response in wild type mice

The misfolding and aggregation of the tau protein into neurofibrillary tangles constitutes a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs. However, the mechanisms orchestrating the dissemination of TBI brain-derived tau polymorphs (TBI-BDTPs) remain elusive. In this study, we explored whether TBI-BDTPs could initiate pathological tau formation, leading to distinct pathogenic trajectories. Wild-type mice were exposed to TBI-BDTPs from sham, single-blast (SB), or repeated-blast (RB) conditions, and their memory function was assessed through behavioral assays at 2- and 8-month post-injection. Our findings revealed that RB-BDTPs induced cognitive and motor deficits, concurrently fostering the emergence of toxic tau aggregates within the injected hippocampus. Strikingly, this tau pathology propagated to cortical layers, intensifying over time. Importantly, RB-BDTP-exposed animals displayed heightened glial cell activation, NLRP3 inflammasome formation, and increased TBI biomarkers, particularly triggering the aggregation of S100B, which is indicative of a neuroinflammatory response. Collectively, our results shed light on the intricate mechanisms underlying TBI-BDTP-induced tau pathology and its association with neuroinflammatory processes. This investigation enhances our understanding of tauopathies and their interplay with neurodegenerative and inflammatory pathways following traumatic brain injury.

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来源期刊
Progress in Neurobiology
Progress in Neurobiology 医学-神经科学
CiteScore
12.80
自引率
1.50%
发文量
107
审稿时长
33 days
期刊介绍: Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.
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