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Comprehensive multiomics analysis reveals distinct differences between pediatric choroid plexus papilloma and carcinoma. 多组学综合分析揭示了小儿脉络丛乳头状瘤和癌之间的明显差异。
IF 6.2 2区 医学 Q1 Medicine Pub Date : 2024-06-12 DOI: 10.1186/s40478-024-01814-y
Yeonsong Choi, Seung Ah Choi, Eun Jung Koh, Ilsun Yun, Suhyun Park, Sungwon Jeon, Yeonkyung Kim, Sangbeen Park, Donggeon Woo, Ji Hoon Phi, Sung-Hye Park, Dong-Seok Kim, Se Hoon Kim, Jung Won Choi, Ji Won Lee, Tae-Young Jung, Jong Bhak, Semin Lee, Seung-Ki Kim

Choroid plexus tumors (CPTs) are intraventricular tumors derived from the choroid plexus epithelium and occur frequently in children. The aim of this study was to investigate the genomic and epigenomic characteristics of CPT and identify the differences between choroid plexus papilloma (CPP) and choroid plexus carcinoma (CPC). We conducted multiomics analyses of 20 CPT patients including CPP and CPC. Multiomics analysis included whole-genome sequencing, whole-transcriptome sequencing, and methylation sequencing. Mutually exclusive TP53 and EPHA7 point mutations, coupled with the amplification of chromosome 1, were exclusively identified in CPC. In contrast, amplification of chromosome 9 was specific to CPP. Differential gene expression analysis uncovered a significant overexpression of genes related to cell cycle regulation and epithelial-mesenchymal transition pathways in CPC compared to CPP. Overexpression of genes associated with tumor metastasis and progression was observed in the CPC subgroup with leptomeningeal dissemination. Furthermore, methylation profiling unveiled hypomethylation in major repeat regions, including long interspersed nuclear elements, short interspersed nuclear elements, long terminal repeats, and retrotransposons in CPC compared to CPP, implying that the loss of epigenetic silencing of transposable elements may play a role in tumorigenesis of CPC. Finally, the differential expression of AK1, regulated by both genomic and epigenomic factors, emerged as a potential contributing factor to the histological difference of CPP against CPC. Our results suggest pronounced genomic and epigenomic disparities between CPP and CPC, providing insights into the pathogenesis of CPT at the molecular level.

脉络丛肿瘤(CPTs)是源自脉络丛上皮的室管膜内肿瘤,常发生于儿童。本研究旨在研究脉络丛肿瘤的基因组和表观基因组特征,并确定脉络丛乳头状瘤(CPP)和脉络丛癌(CPC)之间的差异。我们对 20 例 CPT 患者(包括 CPP 和 CPC)进行了多组学分析。多组学分析包括全基因组测序、全转录组测序和甲基化测序。TP53和EPHA7点突变相互排斥,再加上1号染色体扩增,在CPC中被独家发现。相比之下,9号染色体的扩增是CPP的特异性。差异基因表达分析发现,与 CPP 相比,CPC 中与细胞周期调控和上皮-间质转化通路相关的基因显著过表达。在有脑膜播散的 CPC 亚组中,观察到与肿瘤转移和进展相关的基因表达过高。此外,甲基化分析显示,与 CPP 相比,CPC 中主要重复区(包括长穿插核元件、短穿插核元件、长末端重复序列和逆转录转座子)的甲基化水平较低,这意味着转座元件表观遗传沉默的缺失可能在 CPC 的肿瘤发生中发挥作用。最后,受基因组和表观基因组因素调控的 AK1 的不同表达是导致 CPP 与 CPC 组织学差异的潜在因素。我们的研究结果表明,CPP 和 CPC 之间存在明显的基因组和表观基因组差异,这为从分子水平了解 CPT 的发病机制提供了启示。
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引用次数: 0
Cryo-EM structures reveal tau filaments from Down syndrome adopt Alzheimer's disease fold. 低温电子显微镜结构揭示了唐氏综合症患者的 tau 纤维采用阿尔茨海默病的折叠结构。
IF 6.2 2区 医学 Q1 Medicine Pub Date : 2024-06-12 DOI: 10.1186/s40478-024-01806-y
Ujjayini Ghosh, Eric Tse, Hyunjun Yang, Marie Shi, Christoffer D Caro, Feng Wang, Gregory E Merz, Stanley B Prusiner, Daniel R Southworth, Carlo Condello

Down syndrome (DS) is a common genetic condition caused by trisomy of chromosome 21. Among their complex clinical features, including musculoskeletal, neurological, and cardiovascular disabilities, individuals with DS have an increased risk of developing progressive dementia and early-onset Alzheimer's disease (AD). This dementia is attributed to the increased gene dosage of the amyloid-β (Aβ) precursor protein gene, the formation of self-propagating Aβ and tau prion conformers, and the deposition of neurotoxic Aβ plaques and tau neurofibrillary tangles. Tau amyloid fibrils have previously been established to adopt many distinct conformations across different neurodegenerative conditions. Here, we report the characterization of brain samples from four DS cases spanning 36-63 years of age by spectral confocal imaging with conformation-specific dyes and cryo-electron microscopy (cryo-EM) to determine structures of isolated tau fibrils. High-resolution structures revealed paired helical filament (PHF) and straight filament (SF) conformations of tau that were identical to those determined from AD cases. The PHFs and SFs are made of two C-shaped protofilaments, each containing a cross-β/β-helix motif. Similar to filaments from AD cases, most filaments from the DS cases adopted the PHF form, while a minority (approximately 20%) formed SFs. Samples from the youngest individual with no documented dementia had sparse tau deposits. To isolate tau for cryo-EM from this challenging sample we used a novel affinity-grid method involving a graphene oxide surface derivatized with anti-tau antibodies. This method improved isolation and revealed that primarily tau PHFs and a minor population of chronic traumatic encephalopathy type II-like filaments were present in this youngest case. These findings expand the similarities between AD and DS to the molecular level, providing insight into their related pathologies and the potential for targeting common tau filament folds by small-molecule therapeutics and diagnostics.

唐氏综合征(DS)是由 21 号染色体三体综合征引起的一种常见遗传病。唐氏综合征患者具有复杂的临床特征,包括肌肉骨骼、神经和心血管方面的残疾,而且患进行性痴呆和早发性阿尔茨海默病(AD)的风险也会增加。这种痴呆症是由于淀粉样蛋白-β(Aβ)前体蛋白基因的基因剂量增加、Aβ和tau朊病毒构象的自我传播形成、以及具有神经毒性的Aβ斑块和tau神经纤维缠结的沉积造成的。Tau 淀粉样蛋白纤维此前已被证实在不同的神经退行性疾病中具有多种不同的构象。在此,我们报告了利用构象特异性染料和冷冻电镜(cryo-EM)对四例年龄在36-63岁之间的DS患者的脑样本进行光谱共聚焦成像的特征描述,以确定分离的tau纤维的结构。高分辨率结构显示了tau的成对螺旋丝(PHF)和直丝(SF)构象,这些构象与从AD病例中确定的构象完全相同。PHF和SF由两条C形原纤维组成,每条原纤维都包含一个交叉β/β-螺旋图案。与AD病例中的细丝相似,DS病例中的大多数细丝采用PHF形式,而少数(约20%)形成SF。没有痴呆症记录的最年轻个体的样本中tau沉积稀少。为了从这一具有挑战性的样本中分离出 tau 进行低温电子显微镜分析,我们使用了一种新颖的亲和格栅方法,该方法涉及用抗 tau 抗体衍生的氧化石墨烯表面。这种方法提高了分离效果,并发现在这个最年轻的病例中,主要存在tau PHFs和少量慢性创伤性脑病II型样丝。这些发现将AD和DS的相似性扩展到了分子水平,使人们对它们的相关病理有了更深入的了解,并有可能通过小分子疗法和诊断方法靶向共同的tau丝褶皱。
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引用次数: 0
Correction: SNCA genetic lowering reveals differential cognitive function of alpha-synuclein dependent on sex. 更正:SNCA基因降低显示α-突触核蛋白的认知功能因性别而异。
IF 7.1 2区 医学 Q1 Medicine Pub Date : 2024-06-11 DOI: 10.1186/s40478-024-01789-w
Jennifer L Brown, Damyan W Hart, Gabriel E Boyle, Taylor G Brown, Michael LaCroix, Andrés M Baraibar, Ross Pelzel, Minwoo Kim, Mathew A Sherman, Samuel Boes, Michelle Sung, Tracy Cole, Michael K Lee, Alfonso Araque, Sylvain E Lesné
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引用次数: 0
A multiverse of α-synuclein: investigation of prion strain properties with carboxyl-terminal truncation specific antibodies in animal models. α-突触核蛋白的多重宇宙:在动物模型中使用羧基末端截断特异性抗体研究朊病毒株的特性。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-06-10 DOI: 10.1186/s40478-024-01805-z
Grace M Lloyd, Stephan Quintin, Zachary A Sorrentino, Kimberly-Marie M Gorion, Brach M Bell, Brooke Long, Giavanna Paterno, Benoit I Giasson

Synucleinopathies are a group of neurodegenerative disorders characterized by the presence of misfolded α-Synuclein (αSyn) in the brain. These conditions manifest with diverse clinical and pathophysiological characteristics. This disease diversity is hypothesized to be driven by αSyn strains with differing biophysical properties, potentially influencing prion-type propagation and consequentially the progression of illness. Previously, we investigated this hypothesis by injecting brain lysate (seeds) from deceased individuals with various synucleinopathies or human recombinant αSyn preformed fibrils (PFFs) into transgenic mice overexpressing either wild type or A53T human αSyn. In the studies herein, we expanded on these experiments, utilizing a panel of antibodies specific for the major carboxyl-terminally truncated forms of αSyn (αSynΔC). These modified forms of αSyn are found enriched in human disease brains to inform on potential strain-specific proteolytic patterns. With monoclonal antibodies specific for human αSyn cleaved at residues 103, 114, 122, 125, and 129, we demonstrate that multiple system atrophy (MSA) seeds and PFFs induce differing neuroanatomical spread of αSyn pathology associated with host specific profiles. Overall, αSyn cleaved at residue 103 was most widely present in the induced pathological inclusions. Furthermore, αSynΔC-positive inclusions were present in astrocytes, but more frequently in activated microglia, with patterns dependent on host and inoculum. These findings support the hypothesis that synucleinopathy heterogeneity might stem from αSyn strains with unique biochemical properties that include proteolytic processing, which could result in dominant strain properties.

突触核蛋白病是一组神经退行性疾病,其特征是大脑中存在折叠错误的α-突触核蛋白(αSyn)。这些疾病具有不同的临床和病理生理学特征。据推测,这种疾病的多样性是由具有不同生物物理特性的αSyn菌株驱动的,它们可能会影响朊病毒型的传播,进而影响疾病的进展。在此之前,我们通过向过表达野生型或 A53T 人类 αSyn 的转基因小鼠注射来自各种突触核蛋白病死者的脑裂解物(种子)或人类重组 αSyn 预成纤维(PFFs)来研究这一假设。在本文的研究中,我们扩展了这些实验,使用了一组针对αSyn(αSynΔC)主要羧基末端截短形式的特异性抗体。这些修饰形式的αSyn在人类疾病大脑中富集,可为潜在的特定菌株蛋白水解模式提供信息。利用特异性的单克隆抗体裂解残基 103、114、122、125 和 129 上的人αSyn,我们证明多系统萎缩(MSA)种子和 PFFs 会诱发与宿主特异性特征相关的不同神经解剖学分布的αSyn 病理学。总体而言,在诱导的病理包涵体中,残基 103 处裂解的 αSyn 最为广泛。此外,αSynΔC 阳性包涵体存在于星形胶质细胞中,但在活化的小胶质细胞中更为常见,其模式取决于宿主和接种体。这些发现支持了这样的假设,即突触核蛋白病的异质性可能源于αSyn菌株具有独特的生化特性,包括蛋白水解加工,这可能导致优势菌株特性。
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引用次数: 0
Mitochondrial alterations in fibroblasts from sporadic Alzheimer's disease (AD) patients correlate with AD-related clinical hallmarks. 散发性阿尔茨海默病(AD)患者成纤维细胞中线粒体的改变与 AD 相关临床特征相关。
IF 6.2 2区 医学 Q1 Medicine Pub Date : 2024-06-08 DOI: 10.1186/s40478-024-01807-x
Fanny Eysert, Paula-Fernanda Kinoshita, Julien Lagarde, Sandra Lacas-Gervais, Laura Xicota, Guillaume Dorothée, Michel Bottlaender, Frédéric Checler, Marie-Claude Potier, Marie Sarazin, Mounia Chami

Mitochondrial dysfunctions are key features of Alzheimer's disease (AD). The occurrence of these disturbances in the peripheral cells of AD patients and their potential correlation with disease progression are underinvestigated. We studied mitochondrial structure, function and mitophagy in fibroblasts from healthy volunteers and AD patients at the prodromal (AD-MCI) or demented (AD-D) stages. We carried out correlation studies with clinical cognitive scores, namely, (i) Mini-Mental State Examination (MMSE) and (ii) Dementia Rating-Scale Sum of Boxes (CDR-SOB), and with (iii) amyloid beta (Aβ) plaque burden (PiB-PET imaging) and (iv) the accumulation of peripheral amyloid precursor protein C-terminal fragments (APP-CTFs). We revealed alterations in mitochondrial structure as well as specific mitochondrial dysfunction signatures in AD-MCI and AD-D fibroblasts and revealed that defective mitophagy and autophagy are linked to impaired lysosomal activity in AD-D fibroblasts. We reported significant correlations of a subset of these dysfunctions with cognitive decline, AD-related clinical hallmarks and peripheral APP-CTFs accumulation. This study emphasizes the potential use of peripheral cells for investigating AD pathophysiology.

线粒体功能障碍是阿尔茨海默病(AD)的主要特征。关于这些障碍在阿尔茨海默病患者外周细胞中的发生情况及其与疾病进展的潜在相关性,我们的研究还不够深入。我们研究了健康志愿者和处于前驱期(AD-MCI)或痴呆期(AD-D)的阿氏症患者成纤维细胞的线粒体结构、功能和有丝分裂。我们进行了与临床认知评分的相关性研究,即(i) Mini-Mental State Examination (MMSE)和(ii) Dementia Rating-Scale Sum of Boxes (CDR-SOB),以及与(iii) amyloid beta (Aβ) plaque burden (PiB-PET imaging) 和(iv) peripheral amyloid precursor protein C-terminal fragments (APP-CTFs) 的相关性研究。我们揭示了AD-MCI和AD-D成纤维细胞线粒体结构的改变以及特定的线粒体功能障碍特征,并发现有丝分裂和自噬缺陷与AD-D成纤维细胞溶酶体活性受损有关。我们报告了这些功能障碍的一个子集与认知能力下降、AD 相关临床特征和外周 APP-CTFs 积累之间的重要相关性。这项研究强调了外周细胞在研究AD病理生理学方面的潜在用途。
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引用次数: 0
Tau modulation through AAV9 therapy augments Akt/Erk survival signalling in glaucoma mitigating the retinal degenerative phenotype. 通过 AAV9 疗法调节 Tau 可增强青光眼中 Akt/Erk 的存活信号,减轻视网膜变性表型。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-06-07 DOI: 10.1186/s40478-024-01804-0
Kanishka Pushpitha Maha Thananthirige, Nitin Chitranshi, Devaraj Basavarajappa, Rashi Rajput, Mojdeh Abbasi, Viswanthram Palanivel, Veer Bala Gupta, Joao A Paulo, Maya Koronyo-Hamaoui, Mehdi Mirzaei, Stuart L Graham, Vivek Gupta

The microtubule-associated protein Tau is a key player in various neurodegenerative conditions, including Alzheimer's disease (AD) and Tauopathies, where its hyperphosphorylation disrupts neuronal microtubular lattice stability. Glaucoma, a neurodegenerative disorder affecting the retina, leads to irreversible vision loss by damaging retinal ganglion cells and the optic nerve, often associated with increased intraocular pressure. Prior studies have indicated Tau expression and phosphorylation alterations in the retina in both AD and glaucoma, yet the causative or downstream nature of Tau protein changes in these pathologies remains unclear. This study investigates the impact of Tau protein modulation on retinal neurons under normal and experimental glaucoma conditions. Employing AAV9-mediated gene therapy for Tau overexpression and knockdown, both manipulations were found to adversely affect retinal structural and functional measures as well as neuroprotective Akt/Erk survival signalling in healthy conditions. In the experimental glaucoma model, Tau overexpression intensified inner retinal degeneration, while Tau silencing provided significant protection against these degenerative changes. These findings underscore the critical role of endogenous Tau protein levels in preserving retinal integrity and emphasize the therapeutic potential of targeting Tau in glaucoma pathology.

微管相关蛋白 Tau 是各种神经退行性疾病(包括阿尔茨海默病(AD)和 Tauopathies)的关键因素,其过度磷酸化会破坏神经元微管晶格的稳定性。青光眼是一种影响视网膜的神经退行性疾病,通过损害视网膜神经节细胞和视神经导致不可逆的视力丧失,通常与眼压升高有关。先前的研究表明,AD 和青光眼视网膜中的 Tau 表达和磷酸化都发生了改变,但 Tau 蛋白变化在这些病症中的致病性或下游性质仍不清楚。本研究探讨了正常和实验性青光眼条件下 Tau 蛋白调节对视网膜神经元的影响。利用 AAV9 介导的基因疗法来实现 Tau 的过表达和敲除,结果发现这两种操作都会对视网膜的结构和功能措施以及健康条件下的神经保护性 Akt/Erk 生存信号产生不利影响。在实验性青光眼模型中,Tau过表达会加剧视网膜内层的退化,而Tau沉默则能显著保护视网膜免受这些退化性变化的影响。这些发现强调了内源性 Tau 蛋白水平在维护视网膜完整性方面的关键作用,并强调了在青光眼病理中靶向 Tau 的治疗潜力。
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引用次数: 0
Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy 通过组织内多尺度三维电子显微镜观察亨廷顿症小鼠模型线粒体网络的破坏情况
IF 7.1 2区 医学 Q1 Medicine Pub Date : 2024-06-05 DOI: 10.1186/s40478-024-01802-2
Eva Martin-Solana, Laura Casado-Zueras, Teobaldo E. Torres, Gerardo F. Goya, Maria-Rosario Fernandez-Fernandez, Jose-Jesus Fernandez
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.
亨廷顿氏病(Huntington's disease,HD)是一种遗传性神经退行性疾病,由亨廷丁蛋白编码序列中一个扩展的 CAG 重复序列引起。最初,它主要影响纹状体的中型棘神经元(MSSN)。目前尚无有效的治疗方法,因此需要寻找潜在的治疗靶点。虽然有证据表明线粒体结构在 HD 中发生了改变,但以往的研究主要采用二维方法,而且是在严格的原生脑环境之外进行的。在本研究中,我们采用了一种新颖的多尺度方法,对 HD 小鼠模型的线粒体紊乱进行了全面的三维原位结构分析。我们利用最先进的三维成像技术,特别是用于神经元体部完整成像的 FIB/SEM 技术和用于详细形态学检查的电子断层扫描技术,以及基于图像处理的定量分析技术,在最佳结构条件下研究了脑组织内的 MSSN。我们的研究结果表明,线粒体网络在 HD 中发生了分裂破坏。在健康状态下观察到的交错、细长的线粒体网络转变为孤立、肿胀和短小的实体,内部嵴紊乱、出现空洞和异常大的基质颗粒。
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引用次数: 0
Torpor induces reversible tau hyperphosphorylation and accumulation in mice expressing human tau. 在表达人类 tau 的小鼠中,冬眠会诱导可逆的 tau 过度磷酸化和积累。
IF 6.2 2区 医学 Q1 Medicine Pub Date : 2024-06-04 DOI: 10.1186/s40478-024-01800-4
C F de Veij Mestdagh, M E Witte, W Scheper, A B Smit, R H Henning, R E van Kesteren

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies.

Tau 蛋白过度磷酸化和聚集是神经退行性 Tau 病(如阿尔茨海默病)的主要病理现象。有趣的是,季节性冬眠者在冬眠(即冬眠时的低体温和低代谢状态)期间会出现广泛的 Tau 蛋白高磷酸化,而在唤醒期间则会完全逆转。逆转tau高磷酸化的冬眠相关机制可能具有治疗意义,但目前还不清楚这些机制在多大程度上适用于人类tau。在这里,我们利用表达小鼠tau(mtau)的野生型小鼠和缺乏mtau表达而表达人tau(htau)的小鼠的每日倦怠来解决这个问题。采用AT8、AT100和Ser396免疫印迹法和免疫组织化学法评估临床相关磷酸化位点的tau(高)磷酸化。我们发现,torpor能使mtau和htau小鼠体内磷酸化tau的水平强劲而可逆地升高。免疫组化显示,海马、顶叶后皮层、梨状皮层和杏仁核皮层这四个脑区出现了显著的tau磷酸化现象。野生型小鼠在休眠期主要表现为弥漫有序的高磷酸化tau水平升高,而htau小鼠则含有明显的AT8反应性体细胞树突聚集,类似于在阿尔茨海默氏症大脑中观察到的tau前唐。有趣的是,AT8阳性积聚在唤醒后消失了,而且唤醒后24小时的tau磷酸化水平低于基线观察到的水平,这表明冬眠-唤醒周期对先前存在的高磷酸化tau有有益影响。总之,在与神经退行性病变相关的小鼠模型中,小鼠的日常休眠为研究tau磷酸化、积累和清除提供了一种快速、标准化的方法,同时也为发现治疗人类tau病的新靶点提供了机会。
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引用次数: 0
Correction to: Anatomic survey of seeding in Alzheimer's disease brains reveals unexpected patterns. 更正:对阿尔茨海默病大脑播种的解剖调查揭示了意想不到的模式。
IF 7.1 2区 医学 Q1 Medicine Pub Date : 2024-06-04 DOI: 10.1186/s40478-024-01795-y
Barbara E Stopschinski, Kelly Del Tredici, Sandi-Jo Estill-Terpack, Estifanos Ghebremedhin, Fang F Yu, Heiko Braak, Marc I Diamond
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引用次数: 0
Biomarker evidence of early vision and rod energy-linked pathophysiology benefits from very low dose DMSO in 5xFAD mice. 生物标记证据表明,5xFAD 小鼠的早期视力和杆状能量相关病理生理学可从极低剂量的二甲基亚砜中获益。
IF 6.2 2区 医学 Q1 Medicine Pub Date : 2024-05-31 DOI: 10.1186/s40478-024-01799-8
Bruce A Berkowitz, Anuhya Paruchuri, Josh Stanek, Mura Abdul-Nabi, Robert H Podolsky, Abner Heredia Bustos, Karen Lins Childers, Geoffrey G Murphy, Katherine Stangis, Robin Roberts

Here, we test whether early visual and OCT rod energy-linked biomarkers indicating pathophysiology in nicotinamide nucleotide transhydrogenase (Nnt)-null 5xFAD mice also occur in Nnt-intact 5xFAD mice and whether these biomarkers can be pharmacologically treated. Four-month-old wild-type or 5xFAD C57BL/6 substrains with either a null (B6J) Nnt or intact Nnt gene (B6NTac) and 5xFAD B6J mice treated for one month with either R-carvedilol + vehicle or only vehicle (0.01% DMSO) were studied. The contrast sensitivity (CS), external limiting membrane-retinal pigment epithelium (ELM-RPE) thickness (a proxy for low pH-triggered water removal), profile shape of the hyperreflective band just posterior to the ELM (i.e., the mitochondrial configuration within photoreceptors per aspect ratio [MCP/AR]), and retinal laminar thickness were measured. Both wild-type substrains showed similar visual performance indices and dark-evoked ELM-RPE contraction. The lack of a light-dark change in B6NTac MCP/AR, unlike in B6J mice, is consistent with relatively greater mitochondrial efficiency. 5xFAD B6J mice, but not 5xFAD B6NTac mice, showed lower-than-WT CS. Light-adapted 5xFAD substrains both showed abnormal ELM-RPE contraction and greater-than-WT MCP/AR contraction. The inner retina and superior outer retina were thinner. Treating 5xFAD B6J mice with R-carvedilol + DMSO or DMSO alone corrected CS and ELM-RPE contraction but not supernormal MCP/AR contraction or laminar thinning. These results provide biomarker evidence for prodromal photoreceptor mitochondrial dysfunction/oxidative stress/oxidative damage, which is unrelated to visual performance, as well as the presence of the Nnt gene. This pathophysiology is druggable in 5xFAD mice.

在这里,我们测试了烟酰胺核苷酸转氢酶(Nnt)无效的 5xFAD 小鼠是否也会出现表明病理生理学的早期视觉和 OCT 杆状能量相关生物标记物,以及这些生物标记物是否可以通过药物治疗。研究对象是四个月大的野生型或 5xFAD C57BL/6 亚系的 Nnt 基因无效(B6J)或完整的 Nnt 基因(B6NTac)小鼠,以及用 R-carvedilol + 车辆或仅用车辆(0.01% DMSO)治疗一个月的 5xFAD B6J 小鼠。研究人员测量了小鼠的对比敏感度(CS)、外部限界膜-视网膜色素上皮(ELM-RPE)厚度(低pH值触发的水分去除的代表)、ELM正后方高反射带的轮廓形状(即感光器内线粒体配置的单位长宽比[MCP/AR])以及视网膜板层厚度。两个野生型亚系都表现出相似的视觉表现指数和暗诱发的ELM-RPE收缩。与 B6J 小鼠不同的是,B6NTac MCP/AR 没有光-暗变化,这与线粒体效率相对较高是一致的。5xFAD B6J 小鼠的 CS 值低于 WT 值,而 5xFAD B6NTac 小鼠的 CS 值则低于 WT 值。光适应 5xFAD 亚系均表现出异常的 ELM-RPE 收缩和高于 WT 的 MCP/AR 收缩。视网膜内层和视网膜外层较薄。用 R-carvedilol + DMSO 或仅用 DMSO 治疗 5xFAD B6J 小鼠可纠正 CS 和 ELM-RPE 收缩,但不能纠正 MCP/AR 超常收缩或薄层化。这些结果为前驱光感受器线粒体功能障碍/氧化应激/氧化损伤提供了生物标志物证据,这与视觉表现以及 Nnt 基因的存在无关。5xFAD 小鼠的这种病理生理学是可以药物治疗的。
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Acta Neuropathologica Communications
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