Translational Neurodegeneration最新文献_第5页

Putative novel CSF biomarkers of Alzheimer's disease based on the novel concept of generic protein misfolding and proteotoxicity: the PRAMA cohort. 基于通用蛋白质错误折叠和蛋白质毒性新概念的阿尔茨海默病 CSF 潜在新型生物标志物：PRAMA 队列。

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-03-08 DOI: 10.1186/s40035-024-00405-0

Alessandra Bigi, Giulia Fani, Valentina Bessi, Liliana Napolitano, Silvia Bagnoli, Assunta Ingannato, Lorenzo Neri, Roberta Cascella, Paolo Matteini, Sandro Sorbi, Benedetta Nacmias, Cristina Cecchi, Fabrizio Chiti

引用次数: 0

LRRK2 kinase inhibition reverses G2019S mutation-dependent effects on tau pathology progression 抑制 LRRK2 激酶可逆转 G2019S 突变对 tau 病理学进展的依赖性影响

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-03-04 DOI: 10.1186/s40035-024-00403-2

Noah Lubben, Julia K. Brynildsen, Connor M. Webb, Howard L. Li, Cheryl E. G. Leyns, Lakshmi Changolkar, Bin Zhang, Emily S. Meymand, Mia O’Reilly, Zach Madaj, Daniella DeWeerd, Matthew J. Fell, Virginia M. Y. Lee, Dani S. Bassett, Michael X. Henderson

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson’s disease (PD). These mutations elevate the LRRK2 kinase activity, making LRRK2 kinase inhibitors an attractive therapeutic. LRRK2 kinase activity has been consistently linked to specific cell signaling pathways, mostly related to organelle trafficking and homeostasis, but its relationship to PD pathogenesis has been more difficult to define. LRRK2-PD patients consistently present with loss of dopaminergic neurons in the substantia nigra but show variable development of Lewy body or tau tangle pathology. Animal models carrying LRRK2 mutations do not develop robust PD-related phenotypes spontaneously, hampering the assessment of the efficacy of LRRK2 inhibitors against disease processes. We hypothesized that mutations in LRRK2 may not be directly related to a single disease pathway, but instead may elevate the susceptibility to multiple disease processes, depending on the disease trigger. To test this hypothesis, we have previously evaluated progression of α-synuclein and tau pathologies following injection of proteopathic seeds. We demonstrated that transgenic mice overexpressing mutant LRRK2 show alterations in the brain-wide progression of pathology, especially at older ages. Here, we assess tau pathology progression in relation to long-term LRRK2 kinase inhibition. Wild-type or LRRK2G2019S knock-in mice were injected with tau fibrils and treated with control diet or diet containing LRRK2 kinase inhibitor MLi-2 targeting the IC50 or IC90 of LRRK2 for 3–6 months. Mice were evaluated for tau pathology by brain-wide quantitative pathology in 844 brain regions and subsequent linear diffusion modeling of progression. Consistent with our previous work, we found systemic alterations in the progression of tau pathology in LRRK2G2019S mice, which were most pronounced at 6 months. Importantly, LRRK2 kinase inhibition reversed these effects in LRRK2G2019S mice, but had minimal effect in wild-type mice, suggesting that LRRK2 kinase inhibition is likely to reverse specific disease processes in G2019S mutation carriers. Additional work may be necessary to determine the potential effect in non-carriers. This work supports a protective role of LRRK2 kinase inhibition in G2019S carriers and provides a rational workflow for systematic evaluation of brain-wide phenotypes in therapeutic development.

富亮氨酸重复激酶 2（LRRK2）的突变是家族性帕金森病（PD）最常见的病因。这些突变提高了 LRRK2 激酶的活性，使 LRRK2 激酶抑制剂成为一种极具吸引力的疗法。LRRK2 激酶活性一直与特定的细胞信号通路有关，其中大部分与细胞器的转运和稳态有关，但其与帕金森病发病机制的关系却较难界定。LRRK2-PD 患者始终表现为黑质中多巴胺能神经元的缺失，但路易体或 tau tangle 病理发展各不相同。携带 LRRK2 基因突变的动物模型不会自发形成与帕金森病相关的强大表型，这妨碍了评估 LRRK2 抑制剂对疾病过程的疗效。我们假设，LRRK2 的突变可能与单一疾病通路并不直接相关，相反，它可能会根据疾病的诱发因素提高对多种疾病过程的易感性。为了验证这一假设，我们先前评估了注射蛋白病理种子后α-突触核蛋白和tau病变的进展情况。我们证实，过量表达突变型 LRRK2 的转基因小鼠在整个大脑的病理进展中表现出改变，尤其是在年龄较大时。在此，我们评估了与长期LRRK2激酶抑制有关的tau病理学进展。给野生型小鼠或 LRRK2G2019S 基因敲入小鼠注射 tau 纤维素，并用对照饮食或含有 LRRK2 激酶抑制剂 MLi-2 的饮食（以 LRRK2 的 IC50 或 IC90 为靶点）治疗 3-6 个月。通过对844个脑区进行全脑定量病理学检查和随后的进展线性扩散建模，对小鼠的tau病理学进行评估。与我们之前的工作一致，我们发现 LRRK2G2019S 小鼠的 tau 病理学进展发生了系统性改变，这种改变在 6 个月时最为明显。重要的是，LRRK2 激酶抑制剂能逆转 LRRK2G2019S 小鼠的这些影响，但对野生型小鼠的影响却微乎其微，这表明 LRRK2 激酶抑制剂有可能逆转 G2019S 突变携带者的特定疾病过程。要确定对非携带者的潜在影响，可能还需要做更多的工作。这项研究支持抑制 LRRK2 激酶对 G2019S 基因携带者的保护作用，并为在治疗开发过程中系统评估全脑表型提供了合理的工作流程。

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引用次数: 0

Therapeutics for neurodegenerative diseases by targeting the gut microbiome: from bench to bedside 针对肠道微生物组的神经退行性疾病疗法：从实验室到病床

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-02-27 DOI: 10.1186/s40035-024-00404-1

Yuan-Yuan Ma, Xin Li, Jin-Tai Yu, Yan-Jiang Wang

The aetiologies and origins of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD), are complex and multifaceted. A growing body of evidence suggests that the gut microbiome plays crucial roles in the development and progression of neurodegenerative diseases. Clinicians have come to realize that therapeutics targeting the gut microbiome have the potential to halt the progression of neurodegenerative diseases. This narrative review examines the alterations in the gut microbiome in AD, PD, ALS and HD, highlighting the close relationship between the gut microbiome and the brain in neurodegenerative diseases. Processes that mediate the gut microbiome–brain communication in neurodegenerative diseases, including the immunological, vagus nerve and circulatory pathways, are evaluated. Furthermore, we summarize potential therapeutics for neurodegenerative diseases that modify the gut microbiome and its metabolites, including diets, probiotics and prebiotics, microbial metabolites, antibacterials and faecal microbiome transplantation. Finally, current challenges and future directions are discussed.

阿尔茨海默病（AD）、帕金森病（PD）、肌萎缩侧索硬化症（ALS）和亨廷顿病（HD）等神经退行性疾病的病因和起源是复杂和多方面的。越来越多的证据表明，肠道微生物组在神经退行性疾病的发生和发展过程中起着至关重要的作用。临床医生逐渐认识到，针对肠道微生物组的疗法有可能阻止神经退行性疾病的进展。这篇叙述性综述探讨了 AD、PD、ALS 和 HD 中肠道微生物组的改变，强调了神经退行性疾病中肠道微生物组与大脑之间的密切关系。我们评估了神经退行性疾病中介导肠道微生物组与大脑交流的过程，包括免疫、迷走神经和循环途径。此外，我们还总结了改变肠道微生物组及其代谢物的神经退行性疾病潜在疗法，包括饮食、益生菌和益生元、微生物代谢物、抗菌药和粪便微生物组移植。最后，还讨论了当前的挑战和未来的发展方向。

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引用次数: 0

α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Ca_v3.2 calcium signaling in astrocytes. α-突触核蛋白寡聚体可增强神经炎性 NF-κB 活性并诱导星形胶质细胞中的 Cav3.2 钙信号转导。

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-02-21 DOI: 10.1186/s40035-024-00401-4

Emmanouela Leandrou, Ioanna Chalatsa, Dimitrios Anagnostou, Christina Machalia, Maria Semitekolou, Vicky Filippa, Manousos Makridakis, Antonia Vlahou, Ema Anastasiadou, Kostas Vekrellis, Evangelia Emmanouilidou

Background: It is now realized that Parkinson's disease (PD) pathology extends beyond the substantia nigra, affecting both central and peripheral nervous systems, and exhibits a variety of non-motor symptoms often preceding motor features. Neuroinflammation induced by activated microglia and astrocytes is thought to underlie these manifestations. α-Synuclein aggregation has been linked with sustained neuroinflammation in PD, aggravating neuronal degeneration; however, there is still a lack of critical information about the structural identity of the α-synuclein conformers that activate microglia and/or astrocytes and the molecular pathways involved.

Methods: To investigate the role of α-synuclein conformers in the development and maintenance of neuroinflammation, we used primary quiescent microglia and astrocytes, post-mortem brain tissues from PD patients and A53T α-synuclein transgenic mice that recapitulate key features of PD-related inflammatory responses in the absence of cell death, i.e., increased levels of pro-inflammatory cytokines and complement proteins. Biochemical and -omics techniques including RNAseq and secretomic analyses, combined with 3D reconstruction of individual astrocytes and live calcium imaging, were used to uncover the molecular mechanisms underlying glial responses in the presence of α-synuclein oligomers in vivo and in vitro.

Results: We found that the presence of SDS-resistant hyper-phosphorylated α-synuclein oligomers, but not monomers, was correlated with sustained inflammatory responses, such as elevated levels of endogenous antibodies and cytokines and microglial activation. Similar oligomeric α-synuclein species were found in post-mortem human brain samples of PD patients but not control individuals. Detailed analysis revealed a decrease in Iba1^Low/CD68^Low microglia and robust alterations in astrocyte number and morphology including process retraction. Our data indicated an activation of the p38/ATF2 signaling pathway mostly in microglia and a sustained induction of the NF-κB pathway in astrocytes of A53T mice. The sustained NF-κB activity triggered the upregulation of astrocytic T-type Ca_v3.2 Ca²⁺ channels, altering the astrocytic secretome and promoting the secretion of IGFBPL1, an IGF-1 binding protein with anti-inflammatory and neuroprotective potential.

Conclusions: Our work supports a causative link between the neuron-produced α-synuclein oligomers and sustained neuroinflammation in vivo and maps the signaling pathways that are stimulated in microglia and astrocytes. It also highlights the recruitment of astrocytic Ca_v3.2 channels as a potential neuroprotective mediator against the α-synuclein-induced neuroinflammation.

背景：现在人们意识到，帕金森病（PD）的病理范围超出了黑质，影响到中枢和周围神经系统，并表现出各种非运动症状，这些症状往往出现在运动特征之前。活化的小胶质细胞和星形胶质细胞诱发的神经炎症被认为是这些表现的基础。α-突触核蛋白聚集与帕金森病的持续神经炎症有关，会加重神经元变性；然而，目前仍缺乏有关激活小胶质细胞和/或星形胶质细胞的α-突触核蛋白构象的结构特性以及相关分子途径的关键信息：为了研究α-突触核蛋白构象在神经炎症的发展和维持中的作用，我们使用了原代静止小胶质细胞和星形胶质细胞、帕金森病患者的死后脑组织以及A53T α-突触核蛋白转基因小鼠，这些小鼠在没有细胞死亡的情况下再现了帕金森病相关炎症反应的关键特征，即促炎细胞因子和补体蛋白水平的升高。生化和组学技术包括RNAseq和分泌组学分析，结合单个星形胶质细胞的三维重建和活体钙成像，用于揭示体内和体外α-突触核蛋白寡聚体存在时神经胶质反应的分子机制：我们发现，抗 SDS 超磷酸化 α-突触核蛋白寡聚体（而非单体）的存在与持续的炎症反应相关，如内源性抗体和细胞因子水平升高以及微胶质细胞活化。在帕金森病患者的尸检人脑样本中也发现了类似的α-突触核蛋白低聚物，但对照组没有发现。详细分析显示，Iba1Low/CD68Low 小胶质细胞减少，星形胶质细胞的数量和形态发生了显著变化，包括过程回缩。我们的数据表明，p38/ATF2 信号通路主要在小胶质细胞中被激活，而在 A53T 小鼠的星形胶质细胞中，NF-κB 通路被持续诱导。持续的NF-κB活性引发了星形胶质细胞T型Cav3.2 Ca2+通道的上调，改变了星形胶质细胞的分泌组并促进了IGFBPL1的分泌，IGFBPL1是一种具有抗炎和神经保护潜力的IGF-1结合蛋白：我们的研究证实了神经元产生的α-突触核蛋白寡聚体与体内持续神经炎症之间的因果关系，并绘制了刺激小胶质细胞和星形胶质细胞的信号通路。该研究还强调了星形胶质细胞 Cav3.2 通道的招募是一种潜在的神经保护介质，可抵御α-突触核蛋白诱导的神经炎症。

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引用次数: 0

Emerging role of senescent microglia in brain aging-related neurodegenerative diseases 衰老小胶质细胞在脑衰老相关神经退行性疾病中的新作用

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-02-20 DOI: 10.1186/s40035-024-00402-3

Chan Rim, Min-Jung You, Minyeop Nahm, Min-Soo Kwon

Brain aging is a recognized risk factor for neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease), but the intricate interplay between brain aging and the pathogenesis of these conditions remains inadequately understood. Cellular senescence is considered to contribute to cellular dysfunction and inflammaging. According to the threshold theory of senescent cell accumulation, the vulnerability to neurodegenerative diseases is associated with the rates of senescent cell generation and clearance within the brain. Given the role of microglia in eliminating senescent cells, the accumulation of senescent microglia may lead to the acceleration of brain aging, contributing to inflammaging and increased vulnerability to neurodegenerative diseases. In this review, we propose the idea that the senescence of microglia, which is notably vulnerable to aging, could potentially serve as a central catalyst in the progression of neurodegenerative diseases. The senescent microglia are emerging as a promising target for mitigating neurodegenerative diseases.

大脑衰老是阿尔茨海默病、帕金森病和肌萎缩性脊髓侧索硬化症（ALS，卢伽雷氏病）等神经退行性疾病的公认风险因素，但人们对大脑衰老与这些疾病的发病机制之间错综复杂的相互作用仍然缺乏足够的了解。细胞衰老被认为是导致细胞功能障碍和炎症的原因之一。根据衰老细胞积累的阈值理论，易患神经退行性疾病与大脑内衰老细胞的生成和清除率有关。鉴于小胶质细胞在清除衰老细胞方面的作用，衰老小胶质细胞的积累可能会导致大脑加速衰老，导致炎症和更易患神经退行性疾病。在这篇综述中，我们提出了这样一个观点：小胶质细胞的衰老对衰老具有显著的脆弱性，有可能成为神经退行性疾病进展的核心催化剂。衰老的小胶质细胞正在成为缓解神经退行性疾病的一个有希望的靶点。

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引用次数: 0

Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer's disease and Parkinson's disease. 微结构的完整性反映了阿尔茨海默病和帕金森病患者的去甲肾上腺素能退化。

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-02-09 DOI: 10.1186/s40035-024-00400-5

Chen-Pei Lin, Irene Frigerio, John G J M Bol, Maud M A Bouwman, Alex J Wesseling, Martin J Dahl, Annemieke J M Rozemuller, Ysbrand D van der Werf, Petra J W Pouwels, Wilma D J van de Berg, Laura E Jonkman

Background: Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer's disease (AD) and Parkinson's disease (PD). Diffusion magnetic resonance imaging (MRI) has the potential to evaluate the integrity of the LC noradrenergic system. The aim of the current study was to determine whether the diffusion MRI-measured integrity of the LC and its tracts are sensitive to noradrenergic degeneration in AD and PD.

Methods: Post-mortem in situ T1-weighted and multi-shell diffusion MRI was performed for 9 AD, 14 PD, and 8 control brain donors. Fractional anisotropy (FA) and mean diffusivity were derived from the LC, and from tracts between the LC and the anterior cingulate cortex, the dorsolateral prefrontal cortex (DLPFC), the primary motor cortex (M1) or the hippocampus. Brain tissue sections of the LC and cortical regions were obtained and immunostained for dopamine-beta hydroxylase (DBH) to quantify noradrenergic cell density and fiber load. Group comparisons and correlations between outcome measures were performed using linear regression and partial correlations.

Results: The AD and PD cases showed loss of LC noradrenergic cells and fibers. In the cortex, the AD cases showed increased DBH + immunoreactivity in the DLPFC compared to PD cases and controls, while PD cases showed reduced DBH + immunoreactivity in the M1 compared to controls. Higher FA within the LC was found for AD, which was correlated with loss of noradrenergic cells and fibers in the LC. Increased FA of the LC-DLPFC tract was correlated with LC noradrenergic fiber loss in the combined AD and control group, whereas the increased FA of the LC-M1 tract was correlated with LC noradrenergic neuronal loss in the combined PD and control group. The tract alterations were not correlated with cortical DBH + immunoreactivity.

Conclusions: In AD and PD, the diffusion MRI-detected alterations within the LC and its tracts to the DLPFC and the M1 were associated with local noradrenergic neuronal loss within the LC, rather than noradrenergic changes in the cortex.

背景：脑室（LC）去甲肾上腺素能系统的退化是导致阿尔茨海默病（AD）和帕金森病（PD）临床症状的原因之一。弥散磁共振成像（MRI）可评估LC去甲肾上腺素能系统的完整性。本研究旨在确定弥散磁共振成像测量的 LC 及其束的完整性是否对 AD 和 PD 的去甲肾上腺素能退化敏感：方法：对9名AD患者、14名PD患者和8名对照组大脑供体进行了死后原位T1加权和多壳体弥散MRI检查。从 LC 以及 LC 与前扣带回皮层、背外侧前额叶皮层 (DLPFC)、初级运动皮层 (M1) 或海马之间的束得出分数各向异性 (FA) 和平均扩散率。获取LC和皮质区域的脑组织切片，并对多巴胺-β羟化酶（DBH）进行免疫染色，以量化去甲肾上腺素能细胞密度和纤维负荷。采用线性回归和部分相关性对结果指标进行了组间比较和相关性分析：结果：AD 和 PD 病例显示出 LC 去甲肾上腺素能细胞和纤维的缺失。在皮层中，与帕金森氏症病例和对照组相比，AD 病例在 DLPFC 中显示出更高的 DBH + 免疫反应性，而与对照组相比，帕金森氏症病例在 M1 中显示出更低的 DBH + 免疫反应性。AD患者LC内的FA较高，这与LC中去甲肾上腺素能细胞和纤维的缺失有关。在AD组和对照组中，LC-DLPFC束的FA增加与LC去甲肾上腺素能纤维的缺失相关，而在PD组和对照组中，LC-M1束的FA增加与LC去甲肾上腺素能神经元的缺失相关。这些束的改变与皮质DBH +免疫反应无关：结论：在AD和PD患者中，弥散核磁共振成像检测到的LC及其通向DLPFC和M1的束的改变与LC局部去甲肾上腺素能神经元缺失有关，而非皮质中去甲肾上腺素能的改变。

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引用次数: 0

Life and disease status of patients with Parkinson's disease during and after zero-COVID in China: an online survey. 中国帕金森病患者在零COVID期间和之后的生活和疾病状况：在线调查。

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-02-06 DOI: 10.1186/s40035-024-00399-9

Pei Huang, Yu-Yan Tan, Biao Chen, Hui-Fang Shang, Li-Juan Wang, Chun-Feng Liu, Ling Chen, Ying Chang, Han Wang, Xue-Lian Wang, Xiao-Guang Lei, Li-Fen Yao, Yang Yu, Zheng Ye, Hai-Bo Chen, Sheng-Di Chen

Background: Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy.

Methods: This multicenter cross-sectional study included two online surveys among PD patients in China, from May 30 to June 30 in 2022 and from January 1 to February 28 in 2023, respectively. The survey questionnaires contained four sections: (1) status of COVID-19 infection; (2) impact on motor and non-motor symptoms; (3) impact on daily and social lives; and (4) impact on PD disease management.

Results: A total of 1764 PD patients participated in the first online survey, with 200 patients having lockdown experience and 3 being COVID-19-positive (0.17%). In addition, 537 patients participated in the second online survey, with 467 patients having COVID-19 infection (86.96%). (1) During zero-COVID, all of the COVID-19-positive patients had mild symptoms of COVID-19 and no death was reported. After zero-COVID, 83.51% of the COVID-19-positive patients had mild symptoms. The overall death rate and inpatient mortality rate of COVID-19-positive PD patients were 3.21% and 30.00%, respectively. (2) During zero-COVID, 49.43% of PD patients reported worsening of PD-related symptoms (lockdown vs. unlockdown, 60.50% vs. 48.02%, P = 0.0009). After zero-COVID, 54.93% of PD patients reported worsening of PD-related symptoms (COVID-19 positive vs. COVID-19 negative, 59.31% vs. 25.71%, P < 0.0001). (3) During zero-COVID, 62.36% of patients felt worried, and 'limited outdoor activities' (55.39%) was the top reason for mental health problems. After zero-COVID, 59.03% of patients felt worried, with 'poor health' (58.10%) being the top reason. The PD patients tended to change their daily activities from offline to online, and their economic and caregiver burdens increased both during and after zero-COVID. (4) Most PD patients would like to choose online rehabilitation during (69.56%) and after zero-COVID (69.27%). The demand for online medication purchasing also increased during (47.00%) and after zero-COVID (26.63%).

Conclusions: The COVID-19 pandemic aggravated the motor and non-motor symptoms of PD patients either during or after the zero-COVID policy period. The PD patients also experienced prominent mental health problems, changes in daily activities, and increases in economic and caregiver burdens. The COVID-19 pandemic has changed ways of PD management with increasing demands for online medication purchasing and rehabilitation.

背景：人们对COVID-19大流行在不同阶段对帕金森病（PD）患者的影响知之甚少。本研究旨在评估帕金森病患者在零COVID政策期间和零COVID政策结束后的生活和疾病状况：这项多中心横断面研究包括分别于 2022 年 5 月 30 日至 6 月 30 日和 2023 年 1 月 1 日至 2 月 28 日对中国 PD 患者进行的两次在线调查。调查问卷包括四个部分：（1）COVID-19感染情况；（2）对运动症状和非运动症状的影响；（3）对日常生活和社会生活的影响；（4）对PD疾病管理的影响：共有 1764 名帕金森氏症患者参与了首次在线调查，其中 200 名患者有过封锁经历，3 名患者为 COVID-19 阳性（0.17%）。此外，537 名患者参与了第二次在线调查，467 名患者感染了 COVID-19（86.96%）。(1）在零COVID期间，所有COVID-19阳性患者都有轻微的COVID-19症状，没有死亡报告。零 COVID 之后，83.51%的 COVID-19 阳性患者症状轻微。COVID-19 阳性 PD 患者的总死亡率和住院死亡率分别为 3.21% 和 30.00%。(2）在零 COVID 期间，49.43% 的 PD 患者报告 PD 相关症状恶化（锁定与未锁定相比，60.50% 对 48.02%，P = 0.0009）。零 COVID 后，54.93% 的 PD 患者报告 PD 相关症状恶化（COVID-19 阳性 vs. COVID-19 阴性，59.31% vs. 25.71%，P=0.0009）：在零 COVID 政策期间或之后，COVID-19 大流行加剧了帕金森病患者的运动和非运动症状。此外，帕金森病患者还经历了突出的心理健康问题、日常活动的改变以及经济和护理负担的增加。COVID-19 大流行改变了帕金森病的管理方式，对在线购药和康复的需求不断增加。

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引用次数: 0

The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing. 老龄化与阿尔茨海默氏症之间的相互作用：从老龄化特征中获得的启示。

IF 10.8 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-01-23 DOI: 10.1186/s40035-024-00397-x

Yuqing Liu, Yejun Tan, Zheyu Zhang, Min Yi, Lemei Zhu, Weijun Peng

Ageing is a crucial risk factor for Alzheimer's disease (AD) and is characterised by systemic changes in both intracellular and extracellular microenvironments that affect the entire body instead of a single organ. Understanding the specific mechanisms underlying the role of ageing in disease development can facilitate the treatment of ageing-related diseases, such as AD. Signs of brain ageing have been observed in both AD patients and animal models. Alleviating the pathological changes caused by brain ageing can dramatically ameliorate the amyloid beta- and tau-induced neuropathological and memory impairments, indicating that ageing plays a crucial role in the pathophysiological process of AD. In this review, we summarize the impact of several age-related factors on AD and propose that preventing pathological changes caused by brain ageing is a promising strategy for improving cognitive health.

老龄化是阿尔茨海默病（AD）的一个重要风险因素，其特点是细胞内和细胞外微环境发生系统性变化，影响全身而非单一器官。了解老化在疾病发展中的作用的具体机制，有助于治疗与老化有关的疾病，如老年痴呆症。在注意力缺失症患者和动物模型中都观察到了大脑老化的迹象。缓解脑老化引起的病理变化可显著改善淀粉样β和tau诱导的神经病理学和记忆损伤，这表明老化在AD的病理生理过程中起着至关重要的作用。在这篇综述中，我们总结了几种与年龄相关的因素对AD的影响，并提出预防大脑老化引起的病理变化是改善认知健康的一种有前途的策略。

引用次数: 0

The therapeutic potential of probucol and probucol analogues in neurodegenerative diseases. 丙谷酚和丙谷酚类似物在神经退行性疾病中的治疗潜力。

IF 10.8 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-01-22 DOI: 10.1186/s40035-024-00398-w

Arazu Sharif, John Mamo, Virginie Lam, Hani Al-Salami, Armin Mooranian, Gerald F Watts, Roger Clarnette, Giuseppe Luna, Ryu Takechi

Neurodegenerative disorders present complex pathologies characterized by various interconnected factors, including the aggregation of misfolded proteins, oxidative stress, neuroinflammation and compromised blood-brain barrier (BBB) integrity. Addressing such multifaceted pathways necessitates the development of multi-target therapeutic strategies. Emerging research indicates that probucol, a historic lipid-lowering medication, offers substantial potential in the realm of neurodegenerative disease prevention and treatment. Preclinical investigations have unveiled multifaceted cellular effects of probucol, showcasing its remarkable antioxidative and anti-inflammatory properties, its ability to fortify the BBB and its direct influence on neural preservation and adaptability. These diverse effects collectively translate into enhancements in both motor and cognitive functions. This review provides a comprehensive overview of recent findings highlighting the efficacy of probucol and probucol-related compounds in the context of various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and cognitive impairment associated with diabetes.

神经退行性疾病的病理复杂，以各种相互关联的因素为特征，包括折叠错误的蛋白质聚集、氧化应激、神经炎症和血脑屏障（BBB）完整性受损。要解决这些多方面的途径，就必须开发多靶点治疗策略。新近的研究表明，普罗布考这种历史悠久的降脂药物在预防和治疗神经退行性疾病领域具有巨大的潜力。临床前研究揭示了丙谷醇对细胞的多方面影响，展示了其显著的抗氧化和抗炎特性、强化生物BB的能力以及对神经保护和适应性的直接影响。这些不同的效应共同作用于运动和认知功能的增强。这篇综述全面概述了最近的研究成果，重点介绍了益普糖醇和益普糖醇相关化合物在各种神经退行性疾病（包括阿尔茨海默病、帕金森病、亨廷顿氏病以及与糖尿病相关的认知障碍）中的功效。

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引用次数: 0

Correction: A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau 更正：海马显性和可诱导表达截短人类 tau 的新型转基因小鼠品系

IF 12.6 1区医学 Q1 NEUROSCIENCES

Translational Neurodegeneration

Pub Date : 2024-01-11 DOI: 10.1186/s40035-024-00396-y

Yang Gao, Yuying Wang, Huiyang Lei, Zhendong Xu, Shihong Li, Haitao Yu, Jiazhao Xie, Zhentao Zhang, Gongping Liu, Yao Zhang, Jie Zheng, Jian‑Zhi Wang

Correction: Translational Neurodegeneration 12:51 (2023) https://doi.org/10.1186/s40035-023-00379-5Following publication of the original article [1], the authors reported an error in the Fig. 2:Figure 2e presented a typing error "HT7" was wrongly written as "HT1". See the Fig. 2 corrected<figure><figcaption>Fig. 2</figcaption><picture><source srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40035-024-00396-y/MediaObjects/40035_2024_396_Fig2_HTML.png?as=webp" type="image/webp"/><img alt="figure 1" aria-describedby="Fig1" height="964" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs40035-024-00396-y/MediaObjects/40035_2024_396_Fig2_HTML.png" width="685"/></picture>Increase of phosphorylated tau in the hippocampus of dox-administered hTau368 mice. a Diagram of human tau protein structure and phosphorylation epitopes measured in this study. b, c Dox treatment for 2 months showed no infuence on tau expression and phosphorylation in wild-type mice. Unpaired Student’s t-test, P > 0.05, n = 3 mice in each group. d, e Dox-treated hTau368 mice had higher levels of phosphorylated tau in the RIPA-soluble lysate of hippocampus. Homozygotes showed much more prominent pTau increase than hemizygotes. One-way ANOVA followed by Tukey’s multiple comparisons tests, *P < 0.05, **P < 0.01, ***P < 0.001, compared with the Veh group (n = 4 mice); #P < 0.05, Dox-Homo (n = 3 mice) compared with the Dox-Hemi group (n = 3 mice). f–h pTau aggregation in the hippocampus of Dox-treated hTau368 mice, detected by immunostaining for pS181, pS199 and AT8 tau. One-way ANOVA followed by Tukey’s multiple comparisons tests, ***P < 0.001, n = 3 mice in each group. i, j Dox-treated homozygous hTau368 mice had high levels of pTau in the RIPA-insoluble lysate of hippocampus. One-way ANOVA followed by Tukey’s multiple comparisons tests, *P < 0.05, compared with the Veh group, n = 3–4 mice in each groupFull size image<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-chevron-right-small" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></figure>The original article [1] has been corrected.<ol data-track-component="outbound reference"><li data-counter="1.">Gao Y, Wang Y, Lei H, et al. A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau. Transl Neurodegener. 2023;12:51. https://doi.org/10.1186/s40035-023-00379-5.Article CAS PubMed PubMed Central Google Scholar </li></ol>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg><h3>Authors and Affiliations

Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据，除非在数据的信用行中另有说明。Reprints and permissionsCite this articleGao, Y., Wang, Y., Lei, H. et al. Correction：海马显性诱导表达截短人类 tau 的新型转基因小鼠系。Transl Neurodegener 13, 5 (2024). https://doi.org/10.1186/s40035-024-00396-yDownload citationPublished: 11 January 2024DOI: https://doi.org/10.1186/s40035-024-00396-yShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

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