Current AT(N) stratification for Alzheimer’s disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.
目前阿尔茨海默病（AD）的 AT（N）分层考虑了淀粉样蛋白（A）、tau 蛋白病（T）和神经变性（N）特征的复杂组合。了解这些不同阶段之间的转变是一项重大挑战，特别是考虑到最近疾病调整疗法的发展。这是一项观察性研究，在认知障碍患者的 BALTAZAR 队列和阿尔茨海默病神经影像学倡议（ADNI）中测量了 Tau、pTau181、pTau217、Aβ38/40/42、sAPPα/β、BACE1 和 neurogranin 的 CSF 水平。生物标志物水平与 AT(N) 框架相关。BALTAZAR中的(A)和(T)分别用CSF Aβ42/40比值和pTau217来定义，而ADNI中的(A)和(T)则用淀粉样蛋白和tau PET来定义。(N）在两个队列中均使用 CSF tau 总量定义。不出所料，随着AD从A-T-N-到A + T + N +的连续性，CSF Aβ42逐渐下降。另一方面，Tau 和 pTau181 则随着病情的发展而逐渐增加。从 A + T + N- 到 A + T + N + 的最终转变导致 Aβ38、Aβ42 和 sAPP 水平急剧上升。突触脑脊液生物标志物 BACE1 和神经粒蛋白在最初的 A + T-N- 阶段最低，并随着 T + 和 N + 而增加。两组患者的 CSF pTau181 和总 tau 密切相关。向 A + 表型（A + T-N-）的早期转变主要影响突触功能。T + 和 N + 的出现与阿尔茨海默病病理生物标志物的显著和逐渐增加有关。我们的主要发现是，CSF pTau181 是 N + 而不是 T + 的指标，N + 与 BACE1 蛋白和β-淀粉样肽水平的升高有关。这种升高可能会在正反馈循环中助长淀粉样蛋白级联。总之，我们的数据为了解阿尔茨海默病的淀粉样蛋白、tau 和神经变性等相互关联的病理过程提供了进一步的见解。
{"title":"Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease","authors":"Sylvain Lehmann, Susanna Schraen-Maschke, Luc Buée, Jean-Sébastien Vidal, Constance Delaby, Christophe Hirtz, Frédéric Blanc, Claire Paquet, Bernadette Allinquant, Stéphanie Bombois, Audrey Gabelle, Olivier Hanon","doi":"10.1186/s13024-024-00755-3","DOIUrl":"https://doi.org/10.1186/s13024-024-00755-3","url":null,"abstract":"Current AT(N) stratification for Alzheimer’s disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-08DOI: 10.1186/s13024-024-00757-1
Qi Guo, Lingyan Ping, Eric B. Dammer, Duc M. Duong, Luming Yin, Kaiming Xu, Anantharaman Shantaraman, Edward J. Fox, Todd E Golde, Erik C.B. Johnson, Blaine R. Roberts, James J. Lah, Allan I. Levey, Nicholas T. Seyfried
Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer’s disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches. We employed heparin-affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to enrich HBPs from plasma obtained from AD (n = 62) and control (n = 47) samples. These profiles were then correlated to Aβ, tau and phosphorylated tau (pTau) CSF biomarkers and plasma pTau181 from the same individuals, as well as a consensus brain proteome network to assess the overlap with AD brain pathophysiology. Heparin enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundant proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude in abundance, were measured across 109 samples. Compared to the consensus AD brain protein co-expression network, we observed that specific plasma proteins exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes, highlighting the complex interplay between the two compartments. Elevated proteins in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate with Aβ deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and the APOE4 proteoform. Additionally, heparin-enriched proteins in plasma demonstrated significant correlations with conventional AD CSF biomarkers, including Aβ, total tau, pTau, and plasma pTau181. A panel of five plasma proteins classified AD from control individuals with an area under the curve (AUC) of 0.85. When combined with plasma pTau181, the panel significantly improved the classification performance of pTau181 alone, increasing the AUC from 0.93 to 0.98. This suggests that the heparin-enriched plasma proteome captures additional variance in cognitive dementia beyond what is explained by pTau181. These findings support the utility of a heparin-affinity approach coupled with TMT-MS for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain.
{"title":"Heparin-enriched plasma proteome is significantly altered in Alzheimer’s disease","authors":"Qi Guo, Lingyan Ping, Eric B. Dammer, Duc M. Duong, Luming Yin, Kaiming Xu, Anantharaman Shantaraman, Edward J. Fox, Todd E Golde, Erik C.B. Johnson, Blaine R. Roberts, James J. Lah, Allan I. Levey, Nicholas T. Seyfried","doi":"10.1186/s13024-024-00757-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00757-1","url":null,"abstract":"Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer’s disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches. We employed heparin-affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to enrich HBPs from plasma obtained from AD (n = 62) and control (n = 47) samples. These profiles were then correlated to Aβ, tau and phosphorylated tau (pTau) CSF biomarkers and plasma pTau181 from the same individuals, as well as a consensus brain proteome network to assess the overlap with AD brain pathophysiology. Heparin enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundant proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude in abundance, were measured across 109 samples. Compared to the consensus AD brain protein co-expression network, we observed that specific plasma proteins exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes, highlighting the complex interplay between the two compartments. Elevated proteins in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate with Aβ deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and the APOE4 proteoform. Additionally, heparin-enriched proteins in plasma demonstrated significant correlations with conventional AD CSF biomarkers, including Aβ, total tau, pTau, and plasma pTau181. A panel of five plasma proteins classified AD from control individuals with an area under the curve (AUC) of 0.85. When combined with plasma pTau181, the panel significantly improved the classification performance of pTau181 alone, increasing the AUC from 0.93 to 0.98. This suggests that the heparin-enriched plasma proteome captures additional variance in cognitive dementia beyond what is explained by pTau181. These findings support the utility of a heparin-affinity approach coupled with TMT-MS for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"29 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-27DOI: 10.1186/s13024-024-00754-4
Gabriela Rodriguez Moore, Isabel Melo-Escobar, David Stegner, Oliver Bracko
Alzheimer’s disease (AD) and related dementias (ADRD) collectively affect a significant portion of the aging population worldwide. The pathological progression of AD involves not only the classical hallmarks of amyloid beta (Aβ) plaque buildup and neurofibrillary tangle development but also the effects of vasculature and chronic inflammatory processes. Recently, platelets have emerged as central players in systemic and neuroinflammation. Studies have shown that patients with altered platelet receptor expression exhibit accelerated cognitive decline independent of traditional risk factors. Additionally, platelets from AD patients exhibit heightened unstimulated activation compared to control groups. Platelet granules contain crucial AD-related proteins like tau and amyloid precursor protein (APP). Dysregulation of platelet exocytosis contributes to disease phenotypes characterized by increased bleeding, stroke, and cognitive decline risk. Recent studies have indicated that these effects are not associated with the quantity of platelets present in circulation. This underscores the hypothesis that disruptions in platelet-mediated inflammation and healing processes may play a crucial role in the development of ADRD. A thorough look at platelets, encompassing their receptors, secreted molecules, and diverse roles in inflammatory interactions with other cells in the circulatory system in AD and ADRD, holds promising prospects for disease management and intervention. This review discusses the pivotal roles of platelets in ADRD.
阿尔茨海默病（AD）和相关痴呆症（ADRD）共同影响着全球很大一部分老龄人口。阿尔茨海默病的病理发展不仅包括淀粉样β（Aβ）斑块堆积和神经纤维缠结发展等经典特征，还包括血管和慢性炎症过程的影响。最近，血小板已成为全身性炎症和神经炎症的核心参与者。研究表明，血小板受体表达发生改变的患者会表现出认知能力加速衰退，而不受传统风险因素的影响。此外，与对照组相比，注意力缺失症患者的血小板表现出更强的非刺激性激活。血小板颗粒中含有与阿氏症相关的重要蛋白，如 tau 和淀粉样前体蛋白 (APP)。血小板外泌失调会导致以出血、中风和认知能力下降风险增加为特征的疾病表型。最近的研究表明，这些影响与血液循环中血小板的数量无关。这突显了一个假设，即血小板介导的炎症和愈合过程的紊乱可能在 ADRD 的发展中起着至关重要的作用。全面研究血小板，包括其受体、分泌分子以及在 AD 和 ADRD 循环系统中与其他细胞的炎症相互作用中的各种作用，将为疾病管理和干预带来光明前景。本综述将讨论血小板在 ADRD 中的关键作用。
{"title":"One immune cell to bind them all: platelet contribution to neurodegenerative disease","authors":"Gabriela Rodriguez Moore, Isabel Melo-Escobar, David Stegner, Oliver Bracko","doi":"10.1186/s13024-024-00754-4","DOIUrl":"https://doi.org/10.1186/s13024-024-00754-4","url":null,"abstract":"Alzheimer’s disease (AD) and related dementias (ADRD) collectively affect a significant portion of the aging population worldwide. The pathological progression of AD involves not only the classical hallmarks of amyloid beta (Aβ) plaque buildup and neurofibrillary tangle development but also the effects of vasculature and chronic inflammatory processes. Recently, platelets have emerged as central players in systemic and neuroinflammation. Studies have shown that patients with altered platelet receptor expression exhibit accelerated cognitive decline independent of traditional risk factors. Additionally, platelets from AD patients exhibit heightened unstimulated activation compared to control groups. Platelet granules contain crucial AD-related proteins like tau and amyloid precursor protein (APP). Dysregulation of platelet exocytosis contributes to disease phenotypes characterized by increased bleeding, stroke, and cognitive decline risk. Recent studies have indicated that these effects are not associated with the quantity of platelets present in circulation. This underscores the hypothesis that disruptions in platelet-mediated inflammation and healing processes may play a crucial role in the development of ADRD. A thorough look at platelets, encompassing their receptors, secreted molecules, and diverse roles in inflammatory interactions with other cells in the circulatory system in AD and ADRD, holds promising prospects for disease management and intervention. This review discusses the pivotal roles of platelets in ADRD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"25 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1186/s13024-024-00752-6
Artem Zatcepin, Johannes Gnörich, Boris-Stephan Rauchmann, Laura M. Bartos, Stephan Wagner, Nicolai Franzmeier, Maura Malpetti, Xianyuan Xiang, Yuan Shi, Samira Parhizkar, Maximilian Grosch, Karin Wind-Mark, Sebastian T. Kunte, Leonie Beyer, Carolin Meyer, Desirée Brösamle, Ann-Christin Wendeln, Collins Osei-Sarpong, Steffanie Heindl, Arthur Liesz, Sophia Stoecklein, Gloria Biechele, Anika Finze, Florian Eckenweber, Simon Lindner, Axel Rominger, Peter Bartenstein, Michael Willem, Sabina Tahirovic, Jochen Herms, Katharina Buerger, Mikael Simons, Christian Haass, Rainer Rupprecht, Markus J. Riemenschneider, Nathalie L. Albert, Marc Beyer, Jonas J. Neher, Lars Paeger, Johannes Levin, Günter U. Höglinger, Robert Perneczky, Sibylle I. Ziegler, Matthias Brendel
Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.
小胶质细胞活化是阿尔茨海默病（AD）神经病理学的标志之一，但人们对脑内小胶质细胞区域性相互作用的影响知之甚少。我们假设，健康大脑中的小胶质细胞活化是区域同步的，但在持续的神经退行性疾病中会出现区域不同步。我们探讨了小胶质细胞连接组的存在，并将小胶质细胞非同步化作为一种老年痴呆症生物标志物进行了研究。为了验证这一概念，我们对小鼠进行了小胶质细胞耗竭试验，以检验当小胶质细胞被清除时，18 kDa 转运体蛋白（TSPO）-PET 的区域间相关系数（ICCs）是否会发生变化。接下来，我们评估了小胶质细胞功能障碍和 AD 病理生理学对小鼠大脑中 TSPO-PET ICCs 的影响，然后将其转化为人类 AD 连续数据集。我们将个性化的小胶质细胞失同步指数与认知表现联系起来。最后，我们在小鼠体内进行了单细胞放射追踪（scRadiotracing），以确保所测得的去同步化是由小胶质细胞引起的。小胶质细胞缺失的小鼠在所有脑区都显示出强烈的 ICC 下降，这表明小胶质细胞特异性的非同步化。注意力缺失症小鼠模型显示小胶质细胞同步性明显降低，这与病理改变的大脑区域细胞放射性示踪剂摄取的变异性增加有关。小鼠的 scRadiotracing 显示，TSPO 信号的增加归因于小胶质细胞。通过在淀粉样蛋白模型中对小胶质细胞耗竭的小鼠进行 TSPO-PET 成像和 scRadiotracing，我们首次提供了可以在小鼠大脑中评估小胶质细胞连接组的证据。小胶质细胞的同步性与注意力缺失症的认知能力下降密切相关，可以作为疾病进展的独立个性化生物标记物。
{"title":"Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease","authors":"Artem Zatcepin, Johannes Gnörich, Boris-Stephan Rauchmann, Laura M. Bartos, Stephan Wagner, Nicolai Franzmeier, Maura Malpetti, Xianyuan Xiang, Yuan Shi, Samira Parhizkar, Maximilian Grosch, Karin Wind-Mark, Sebastian T. Kunte, Leonie Beyer, Carolin Meyer, Desirée Brösamle, Ann-Christin Wendeln, Collins Osei-Sarpong, Steffanie Heindl, Arthur Liesz, Sophia Stoecklein, Gloria Biechele, Anika Finze, Florian Eckenweber, Simon Lindner, Axel Rominger, Peter Bartenstein, Michael Willem, Sabina Tahirovic, Jochen Herms, Katharina Buerger, Mikael Simons, Christian Haass, Rainer Rupprecht, Markus J. Riemenschneider, Nathalie L. Albert, Marc Beyer, Jonas J. Neher, Lars Paeger, Johannes Levin, Günter U. Höglinger, Robert Perneczky, Sibylle I. Ziegler, Matthias Brendel","doi":"10.1186/s13024-024-00752-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00752-6","url":null,"abstract":"Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"7 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-29DOI: 10.1186/s13024-024-00751-7
Qiang Chen, Luis Aguirre, Guoming Liang, Huanhuan Zhao, Tao Dong, Felix Borrego, Itziar de Rojas, Qichan Hu, Christopher Reyes, Ling-Yan Su, Bao Zhang, James D. Lechleiter, Harald H. H. Göring, Philip L. De Jager, Joel E. Kleinman, Thomas M. Hyde, Pan P. Li, Agustín Ruiz, Daniel R. Weinberger, Sudha Seshadri, Liang Ma
The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.
APOE 基因是晚发性阿尔茨海默病（LOAD）最强的遗传风险因素。然而，该基因位点的基因调控机制仍未完全定性。为了在 APOE 基因座中发现新的与阿兹海默症相关的功能元件，我们将 SNP 变异与来自人类死后大脑的多组学数据（包括来自 3 个大脑区域和两个血统（欧洲人和非洲人）的 2,179 份 RNA-seq 样本、667 份 DNA 甲基化样本和 ChIP-seq 样本）进行了整合。此外，我们还绘制了人脑发育过程中 APOE 转录物的表达轨迹。我们发现了一种与 AD 相关的 APOE 转录本（jxn1.2.2），该转录本尤其可见于背外侧前额叶皮层（DLPFC）。APOE jxn1.2.2 转录本与脑神经病理学特征、认知障碍以及 DLPFC 中 APOE4 等位基因的存在有关。我们优先选择了两个与 jxn1.2.2 转录本丰度和 DNA 甲基化水平显著相关的独立功能 SNPs（rs157580 和 rs439401）。这两个 SNP 位于活跃的染色质区域，影响脑相关转录因子的结合亲和力。这两个SNP对欧洲和非洲族群的jxn1.2.2转录本具有共同的影响。新的 APOE 功能元件提供了潜在的治疗靶点，并从机理上揭示了疾病的病因。
{"title":"Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease","authors":"Qiang Chen, Luis Aguirre, Guoming Liang, Huanhuan Zhao, Tao Dong, Felix Borrego, Itziar de Rojas, Qichan Hu, Christopher Reyes, Ling-Yan Su, Bao Zhang, James D. Lechleiter, Harald H. H. Göring, Philip L. De Jager, Joel E. Kleinman, Thomas M. Hyde, Pan P. Li, Agustín Ruiz, Daniel R. Weinberger, Sudha Seshadri, Liang Ma","doi":"10.1186/s13024-024-00751-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00751-7","url":null,"abstract":"The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1186/s13024-024-00746-4
Panpan Wang, Yaping Shao, Murad Al-Nusaif, Jun Zhang, Huijia Yang, Yuting Yang, Kunhyok Kim, Song Li, Cong Liu, Huaibin Cai, Weidong Le
<p><strong>Background: </strong>Although WD repeat domain 45 (WDR45) mutations have been linked to <math><mi>β</mi></math> -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system.</p><p><strong>Methods: </strong>To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45<sup>cKO</sup>). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration.</p><p><strong>Results: </strong>Our study of WDR45<sup>cKO</sup> mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits.</p><p><strong>Conclusions: </strong>In this study, we uncovered the molecul
{"title":"Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.","authors":"Panpan Wang, Yaping Shao, Murad Al-Nusaif, Jun Zhang, Huijia Yang, Yuting Yang, Kunhyok Kim, Song Li, Cong Liu, Huaibin Cai, Weidong Le","doi":"10.1186/s13024-024-00746-4","DOIUrl":"10.1186/s13024-024-00746-4","url":null,"abstract":"<p><strong>Background: </strong>Although WD repeat domain 45 (WDR45) mutations have been linked to <math><mi>β</mi></math> -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system.</p><p><strong>Methods: </strong>To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45<sup>cKO</sup>). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration.</p><p><strong>Results: </strong>Our study of WDR45<sup>cKO</sup> mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits.</p><p><strong>Conclusions: </strong>In this study, we uncovered the molecul","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"62"},"PeriodicalIF":14.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-16DOI: 10.1186/s13024-024-00747-3
Hui Wang, Timothy S. Chang, Beth A. Dombroski, Po-Liang Cheng, Vishakha Patil, Leopoldo Valiente-Banuet, Kurt Farrell, Catriona Mclean, Laura Molina-Porcel, Alex Rajput, Peter Paul De Deyn, Nathalie Le Bastard, Marla Gearing, Laura Donker Kaat, John C. Van Swieten, Elise Dopper, Bernardino F. Ghetti, Kathy L. Newell, Claire Troakes, Justo G. de Yébenes, Alberto Rábano-Gutierrez, Tina Meller, Wolfgang H. Oertel, Gesine Respondek, Maria Stamelou, Thomas Arzberger, Sigrun Roeber, Ulrich Müller, Franziska Hopfner, Pau Pastor, Alexis Brice, Alexandra Durr, Isabelle Le Ber, Thomas G. Beach, Geidy E. Serrano, Lili-Naz Hazrati, Irene Litvan, Rosa Rademakers, Owen A. Ross, Douglas Galasko, Adam L. Boxer, Bruce L. Miller, Willian W. Seeley, Vivanna M. Van Deerlin, Edward B. Lee, Charles L. White, Huw Morris, Rohan de Silva, John F. Crary, Alison M. Goate, Jeffrey S. Friedman, Yuk Yee Leung, Giovanni Coppola, Adam C. Naj, Li-San Wang, Clifton Dalgard, Dennis W. Dickson, Günter U. Höglin..
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.
{"title":"Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy","authors":"Hui Wang, Timothy S. Chang, Beth A. Dombroski, Po-Liang Cheng, Vishakha Patil, Leopoldo Valiente-Banuet, Kurt Farrell, Catriona Mclean, Laura Molina-Porcel, Alex Rajput, Peter Paul De Deyn, Nathalie Le Bastard, Marla Gearing, Laura Donker Kaat, John C. Van Swieten, Elise Dopper, Bernardino F. Ghetti, Kathy L. Newell, Claire Troakes, Justo G. de Yébenes, Alberto Rábano-Gutierrez, Tina Meller, Wolfgang H. Oertel, Gesine Respondek, Maria Stamelou, Thomas Arzberger, Sigrun Roeber, Ulrich Müller, Franziska Hopfner, Pau Pastor, Alexis Brice, Alexandra Durr, Isabelle Le Ber, Thomas G. Beach, Geidy E. Serrano, Lili-Naz Hazrati, Irene Litvan, Rosa Rademakers, Owen A. Ross, Douglas Galasko, Adam L. Boxer, Bruce L. Miller, Willian W. Seeley, Vivanna M. Van Deerlin, Edward B. Lee, Charles L. White, Huw Morris, Rohan de Silva, John F. Crary, Alison M. Goate, Jeffrey S. Friedman, Yuk Yee Leung, Giovanni Coppola, Adam C. Naj, Li-San Wang, Clifton Dalgard, Dennis W. Dickson, Günter U. Höglin..","doi":"10.1186/s13024-024-00747-3","DOIUrl":"https://doi.org/10.1186/s13024-024-00747-3","url":null,"abstract":"Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"40 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-06DOI: 10.1186/s13024-024-00749-1
Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, Luming Yin, E. Kathleen Carter, Marla Gearing, Alice Chen-Plotkin, Edward B. Lee, John Q. Trojanowski, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Lenora Higginbotham
Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.
路易体痴呆（LBD）是由帕金森病痴呆（PDD）和路易体痴呆（DLB）组成的一类疾病，在临床和病理上与阿尔茨海默病（AD）有很大的重叠。鉴定路易体痴呆症病理生理学的独特生物标志物可有效促进其诊断、监测和治疗。我们使用定量质谱法（MS）测量了宾夕法尼亚大学尸检收集的 138 个背外侧前额叶皮层（DLPFC）组织中的 9,000 多种蛋白质，这些组织包括对照组、帕金森病（PD）、PDD 和 DLB 诊断组。然后，我们分析了LBD患者的共表达网络蛋白质改变，在两个独立的LBD数据集中验证了这些疾病特征，并将这些发现与在AD病例网络分析中观察到的结果进行了比较。LBD网络揭示了在PDD和DLB中显著改变的许多共表达蛋白群或 "模块"，它们代表了突触、代谢和炎症病理生理学。将经过验证的 LBD 特征与注意力缺失症的特征进行比较，发现了这两种疾病之间的明显差异。值得注意的是，与突触前模块相关的突触核蛋白在 LBD 中升高，而在 AD 中则相对于对照组降低。我们还发现，与神经胶质相关的矩阵组特征在 AD 中持续升高，而在枸杞多糖症中则发生了更多不同程度的改变，最终将枸杞多糖症病例与同时β-淀粉样蛋白沉积负担较低和较高的病例进行了分层。总之，无偏见的网络蛋白质组分析揭示了枸杞多糖大脑额叶皮层的多种病理生理学变化，这些变化不同于AD的改变。这些结果凸显了枸杞多糖脑网络蛋白质组是一种很有前景的生物标志物来源，可以提高临床识别和管理水平。
{"title":"Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease","authors":"Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, Luming Yin, E. Kathleen Carter, Marla Gearing, Alice Chen-Plotkin, Edward B. Lee, John Q. Trojanowski, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Lenora Higginbotham","doi":"10.1186/s13024-024-00749-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00749-1","url":null,"abstract":"Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"22 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1186/s13024-024-00748-2
Thanaphong Phongpreecha, Kavita Mathi, Brenna Cholerton, Eddie J Fox, Natalia Sigal, Camilo Espinosa, Momsen Reincke, Philip Chung, Ling-Jen Hwang, Chandresh R Gajera, Eloise Berson, Amalia Perna, Feng Xie, Chi-Hung Shu, Debapriya Hazra, Divya Channappa, Jeffrey E Dunn, Lucas B Kipp, Kathleen L Poston, Kathleen S Montine, Holden T Maecker, Nima Aghaeepour, Thomas J Montine
Background: Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.
Methods: In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.
Results: The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.
Conclusions and relevance: Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.
{"title":"Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort.","authors":"Thanaphong Phongpreecha, Kavita Mathi, Brenna Cholerton, Eddie J Fox, Natalia Sigal, Camilo Espinosa, Momsen Reincke, Philip Chung, Ling-Jen Hwang, Chandresh R Gajera, Eloise Berson, Amalia Perna, Feng Xie, Chi-Hung Shu, Debapriya Hazra, Divya Channappa, Jeffrey E Dunn, Lucas B Kipp, Kathleen L Poston, Kathleen S Montine, Holden T Maecker, Nima Aghaeepour, Thomas J Montine","doi":"10.1186/s13024-024-00748-2","DOIUrl":"10.1186/s13024-024-00748-2","url":null,"abstract":"<p><strong>Background: </strong>Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.</p><p><strong>Methods: </strong>In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.</p><p><strong>Results: </strong>The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.</p><p><strong>Conclusions and relevance: </strong>Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"59"},"PeriodicalIF":14.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-30DOI: 10.1186/s13024-024-00750-8
Tengfei Guo, Anqi Li, Pan Sun, Zhengbo He, Yue Cai, Guoyu Lan, Lin Liu, Jieyin Li, Jie Yang, Yalin Zhu, Ruiyue Zhao, Xuhui Chen, Dai Shi, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Pengcheng Ran, Xinlu Wang, Kun Sun, Jie Lu, Ying Han
Background: It is not fully established whether plasma β-amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer's disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.
Methods: We recruited 470 older adults and analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ42/Aβ40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ42/Aβ40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.
Results: Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.
Discussion: This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.
{"title":"Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer's disease.","authors":"Tengfei Guo, Anqi Li, Pan Sun, Zhengbo He, Yue Cai, Guoyu Lan, Lin Liu, Jieyin Li, Jie Yang, Yalin Zhu, Ruiyue Zhao, Xuhui Chen, Dai Shi, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Pengcheng Ran, Xinlu Wang, Kun Sun, Jie Lu, Ying Han","doi":"10.1186/s13024-024-00750-8","DOIUrl":"10.1186/s13024-024-00750-8","url":null,"abstract":"<p><strong>Background: </strong>It is not fully established whether plasma β-amyloid(Aβ)<sub>42</sub>/Aβ<sub>40</sub> and phosphorylated Tau<sub>181</sub> (p-Tau<sub>181</sub>) can effectively detect Alzheimer's disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.</p><p><strong>Methods: </strong>We recruited 470 older adults and analyzed plasma Aβ<sub>42</sub>/Aβ<sub>40</sub>, p-Tau<sub>181</sub>, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> and p-Tau<sub>181</sub> thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> (A) and p-Tau<sub>181</sub> (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.</p><p><strong>Results: </strong>Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> and higher plasma p-Tau<sub>181</sub> were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau<sub>181</sub> and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau<sub>181</sub> and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> and higher plasma p-Tau<sub>181</sub> were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ<sub>42</sub>/Aβ<sub>40</sub> and higher plasma p-Tau<sub>181</sub> in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.</p><p><strong>Discussion: </strong>This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"58"},"PeriodicalIF":14.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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