Pub Date : 2024-08-28DOI: 10.1007/s00401-024-02790-2
Pablo Botella Lucena, Michael T. Heneka
Alzheimer´s disease (AD) stands out as the most common chronic neurodegenerative disorder. AD is characterized by progressive cognitive decline and memory loss, with neurodegeneration as its primary pathological feature. The role of neuroinflammation in the disease course has become a focus of intense research. While microglia, the brain’s resident macrophages, have been pivotal to study central immune inflammation, recent evidence underscores the contributions of other cellular entities to the neuroinflammatory process. In this article, we review the inflammatory role of microglia and astrocytes, focusing on their interactions with AD’s core pathologies, amyloid beta deposition, and tau tangle formation. Additionally, we also discuss how different modes of regulated cell death in AD may impact the chronic neuroinflammatory environment. This review aims to highlight the evolving landscape of neuroinflammatory research in AD and underscores the importance of considering multiple cellular contributors when developing new therapeutic strategies.
阿尔茨海默病(AD)是最常见的慢性神经退行性疾病。阿尔茨海默病的主要病理特征是进行性认知能力下降和记忆力减退,神经变性是其主要病理特征。神经炎症在发病过程中的作用已成为研究的热点。虽然小胶质细胞--大脑中的常驻巨噬细胞--在研究中枢免疫炎症中起着关键作用,但最近的证据强调了其他细胞实体对神经炎症过程的贡献。在本文中,我们回顾了小胶质细胞和星形胶质细胞的炎症作用,重点探讨了它们与 AD 核心病理、淀粉样蛋白 beta 沉积和 tau 纠结形成之间的相互作用。此外,我们还讨论了 AD 中不同的细胞死亡调控模式如何影响慢性神经炎症环境。这篇综述旨在突出 AD 神经炎症研究不断发展的现状,并强调在开发新的治疗策略时考虑多种细胞因素的重要性。
{"title":"Inflammatory aspects of Alzheimer’s disease","authors":"Pablo Botella Lucena, Michael T. Heneka","doi":"10.1007/s00401-024-02790-2","DOIUrl":"10.1007/s00401-024-02790-2","url":null,"abstract":"<div><p>Alzheimer´s disease (AD) stands out as the most common chronic neurodegenerative disorder. AD is characterized by progressive cognitive decline and memory loss, with neurodegeneration as its primary pathological feature. The role of neuroinflammation in the disease course has become a focus of intense research. While microglia, the brain’s resident macrophages, have been pivotal to study central immune inflammation, recent evidence underscores the contributions of other cellular entities to the neuroinflammatory process. In this article, we review the inflammatory role of microglia and astrocytes, focusing on their interactions with AD’s core pathologies, amyloid beta deposition, and tau tangle formation. Additionally, we also discuss how different modes of regulated cell death in AD may impact the chronic neuroinflammatory environment. This review aims to highlight the evolving landscape of neuroinflammatory research in AD and underscores the importance of considering multiple cellular contributors when developing new therapeutic strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078738","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 : 2024-08-27DOI: 10.1007/s00401-024-02791-1
Yu Teranishi, Andrey Yurchenko, Suzanne Tran, Philipp Sievers, Fatemeh Rajabi, Singhabahu Ruchith, Samiya Abi-Jaoude, Antoine Blouin, Franck Bielle, Dominique Cazals-Hatem, Felix Sahm, Sergey Nikolaev, Michel Kalamarides, Matthieu Peyre
{"title":"Correlation between natural history and multi-omics profiling of meningiomas in NF2-related schwannomatosis suggests role of methylation group and immune microenvironment in tumor growth rate","authors":"Yu Teranishi, Andrey Yurchenko, Suzanne Tran, Philipp Sievers, Fatemeh Rajabi, Singhabahu Ruchith, Samiya Abi-Jaoude, Antoine Blouin, Franck Bielle, Dominique Cazals-Hatem, Felix Sahm, Sergey Nikolaev, Michel Kalamarides, Matthieu Peyre","doi":"10.1007/s00401-024-02791-1","DOIUrl":"10.1007/s00401-024-02791-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02791-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078737","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 : 2024-08-23DOI: 10.1007/s00401-024-02788-w
Nathan K. Leclair, Calixto-Hope G. Lucas, Kanish Mirchia, Kathleen McCortney, Craig M. Horbinski, David R. Raleigh, Olga Anczukow
{"title":"The RNA-binding protein IGF2BP1 regulates stability of mRNA transcribed from FOXM1 target genes in hypermitotic meningiomas","authors":"Nathan K. Leclair, Calixto-Hope G. Lucas, Kanish Mirchia, Kathleen McCortney, Craig M. Horbinski, David R. Raleigh, Olga Anczukow","doi":"10.1007/s00401-024-02788-w","DOIUrl":"10.1007/s00401-024-02788-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02788-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045645","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 : 2024-08-23DOI: 10.1007/s00401-024-02778-y
Yiyi Ma, Dolly Reyes-Dumeyer, Angel Piriz, Patricia Recio, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Jean Paul G. Vonsattel, Giuseppe Tosto, Andrew F. Teich, Benjamin Ciener, Sandra Leskinen, Sharanya Sivakumar, Michael DeTure, Duara Ranjan, Dennis Dickson, Melissa Murray, Edward Lee, David A. Wolk, Lee-Way Jin, Brittany N. Dugger, Annie Hiniker, Robert A. Rissman, Richard Mayeux, Badri N. Vardarajan
Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10–8), the intergenic region between VRTN and SYNDIG1L (Score = − 37.67, P = 2.25 × 10–9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10–8), PVRL2 (Score = 125.86, P = 1.64 × 10–9), TOMM40 (Score = − 18.58, P = 4.61 × 10–8), and APOE (Score = 75.12, P = 7.26 × 10–26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.
{"title":"Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups","authors":"Yiyi Ma, Dolly Reyes-Dumeyer, Angel Piriz, Patricia Recio, Diones Rivera Mejia, Martin Medrano, Rafael A. Lantigua, Jean Paul G. Vonsattel, Giuseppe Tosto, Andrew F. Teich, Benjamin Ciener, Sandra Leskinen, Sharanya Sivakumar, Michael DeTure, Duara Ranjan, Dennis Dickson, Melissa Murray, Edward Lee, David A. Wolk, Lee-Way Jin, Brittany N. Dugger, Annie Hiniker, Robert A. Rissman, Richard Mayeux, Badri N. Vardarajan","doi":"10.1007/s00401-024-02778-y","DOIUrl":"10.1007/s00401-024-02778-y","url":null,"abstract":"<div><p> Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: <i>ADAM20</i> (Score = 55.19, <i>P</i> = 4.06 × 10<sup>–8</sup>), the intergenic region between <i>VRTN</i> and <i>SYNDIG1L</i> (Score = − 37.67, <i>P</i> = 2.25 × 10<sup>–9</sup>), <i>SPG7</i> (16q24.3) (Score = 40.51, <i>P</i> = 2.23 × 10<sup>–8</sup>), <i>PVRL2</i> (Score = 125.86, <i>P</i> = 1.64 × 10<sup>–9</sup>), <i>TOMM40</i> (Score = − 18.58, <i>P</i> = 4.61 × 10<sup>–8</sup>), and <i>APOE</i> (Score = 75.12, <i>P</i> = 7.26 × 10<sup>–26</sup>). CGSes in <i>PVRL2</i> and <i>APOE</i> were also significant in NHW. Except for <i>ADAM20</i>, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in <i>SPG7, PVRL2,</i> and <i>APOE</i> were also mQTLs in NHW. Except for <i>SYNDIG1L</i> (<i>P</i> = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (<i>P</i> < 0.05), and methylation at <i>VRTN</i> and <i>TOMM40</i> were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of <i>SYNDIG1</i> and <i>TOMM40</i> were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034912","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 : 2024-08-20DOI: 10.1007/s00401-024-02771-5
Jacob Ayers, T. Peter Lopez, Ian T. Steele, Abby Oehler, Rigo Roman-Albarran, Elisa Cleveland, Alex Chong, George A. Carlson, Carlo Condello, Stanley B. Prusiner
Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion–mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat Prnp promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer’s disease and other tau prion disorders.
野生型和突变型tau蛋白都能错误折叠成朊病毒,并在动物和人的中枢神经系统中自我繁殖。为了扩展其他人的研究,我们在表达突变型人类 tau 蛋白(P301S)的转基因(Tg)大鼠中研究了 tau 蛋白朊病毒介导的神经退行性变的分子基础。我们使用大鼠 Prnp 启动子来驱动人类 0N4R 异构体中突变 tau(P301S)的过表达。在转基因Tg12099(+/+)同源大鼠中,突变型人类tau的普遍表达导致磷酸化tau内含物的逐渐积累,包括额叶皮质和边缘系统中的银阳性缠结。Tg12099(+/+)末期大鼠出现了中枢神经系统功能障碍的迹象,表现出严重的神经变性以及杏仁核和梨状皮层的深度萎缩。皮质边缘结构中的 tau 蛋白朊病毒活性增幅最大。与同基因 Tg12099(+/+)大鼠相比,我们发现半杂合子大鼠的突变 tau 含量较低,因此在 2 岁前神经病理学变化很小。值得注意的是,这些半杂合子大鼠可以通过脑内接种重组tau纤维或从患病、年老的同源Tg12099(+/+)大鼠脑匀浆中析出的tau朊病毒而感染。我们的研究表明,Tg12099大鼠体内tau朊病毒的区域性传播和神经变性与人类原发性tau病的情况相似。这些发现似乎有可能促进我们对人类tau病的了解,并有可能为阿尔茨海默病和其他tau朊病毒疾病带来有效的治疗方法。
{"title":"Severe neurodegeneration in brains of transgenic rats producing human tau prions","authors":"Jacob Ayers, T. Peter Lopez, Ian T. Steele, Abby Oehler, Rigo Roman-Albarran, Elisa Cleveland, Alex Chong, George A. Carlson, Carlo Condello, Stanley B. Prusiner","doi":"10.1007/s00401-024-02771-5","DOIUrl":"10.1007/s00401-024-02771-5","url":null,"abstract":"<div><p>Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion–mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat <i>Prnp</i> promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer’s disease and other tau prion disorders.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003326","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 : 2024-08-19DOI: 10.1007/s00401-024-02769-z
Frederique J. Hart de Ruyter, Manon J. A. P. Evers, Tjado H. J. Morrema, Anke A. Dijkstra, Jurre den Haan, Jos W. R. Twisk, Johannes F. de Boer, Philip Scheltens, Femke H. Bouwman, Frank D. Verbraak, Annemieke J. Rozemuller, Jeroen J. M. Hoozemans
<div><p>The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer’s disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer’s disease (<i>n</i> = 17), primary tauopathies (<i>n</i> = 8), synucleinopathies (<i>n</i> = 27), frontotemporal lobar degeneration (<i>n</i> = 8), mixed pathology (<i>n</i> = 11), other neurodegenerative diseases (<i>n</i> = 6), and cognitively normal controls (<i>n</i> = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer’s disease, primary tauopathies and controls with Alzheimer’s disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (<i>n</i> = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (<i>n</i> = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (<i>n</i> = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (<i>n</i> = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates
{"title":"Neuropathological hallmarks in the post-mortem retina of neurodegenerative diseases","authors":"Frederique J. Hart de Ruyter, Manon J. A. P. Evers, Tjado H. J. Morrema, Anke A. Dijkstra, Jurre den Haan, Jos W. R. Twisk, Johannes F. de Boer, Philip Scheltens, Femke H. Bouwman, Frank D. Verbraak, Annemieke J. Rozemuller, Jeroen J. M. Hoozemans","doi":"10.1007/s00401-024-02769-z","DOIUrl":"10.1007/s00401-024-02769-z","url":null,"abstract":"<div><p>The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer’s disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer’s disease (<i>n</i> = 17), primary tauopathies (<i>n</i> = 8), synucleinopathies (<i>n</i> = 27), frontotemporal lobar degeneration (<i>n</i> = 8), mixed pathology (<i>n</i> = 11), other neurodegenerative diseases (<i>n</i> = 6), and cognitively normal controls (<i>n</i> = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer’s disease, primary tauopathies and controls with Alzheimer’s disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (<i>n</i> = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (<i>n</i> = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (<i>n</i> = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (<i>n</i> = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003325","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}
Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in NOTCH2NLC gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of NOTCH2NLC in mice: the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration.
{"title":"Microglia contribute to polyG-dependent neurodegeneration in neuronal intranuclear inclusion disease","authors":"Shaoping Zhong, Yangye Lian, Binbin Zhou, Ruiqing Ren, Lewei Duan, Yuyin Pan, Yuchen Gong, Xiaoling Wu, Dengfeng Cheng, Puming Zhang, Boxun Lu, Xin Wang, Jing Ding","doi":"10.1007/s00401-024-02776-0","DOIUrl":"10.1007/s00401-024-02776-0","url":null,"abstract":"<div><p>Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder caused by the expansion of GGC trinucleotide repeats in <i>NOTCH2NLC</i> gene. Despite identifying uN2CpolyG, a toxic polyglycine (polyG) protein translated by expanded GGC repeats, the exact pathogenic mechanisms of NIID remain unclear. In this study, we investigated the role of polyG by expressing various forms of <i>NOTCH2NLC</i> in mice: the wild-type, the expanded form with 100 GGC repeats (either translating or not translating into uN2CpolyG), and the mutated form that encodes a pure polyG without GGC-repeat RNA and the C-terminal stretch (uN2CpolyG-dCT). Both uN2CpolyG and uN2CpolyG-dCT induced the formation of inclusions composed by filamentous materials and resulted in neurodegenerative phenotypes in mice, including impaired motor and cognitive performance, shortened lifespan, and pathologic lesions such as white-matter lesions, microgliosis, and astrogliosis. In contrast, expressing GGC-repeat RNA alone was non-pathogenic. Through bulk and single-nuclei RNA sequencing, we identified common molecular signatures linked to the expression of uN2CpolyG and uN2CpolyG-dCT, particularly the upregulation of inflammation and microglia markers, and the downregulation of immediate early genes and splicing factors. Importantly, microglia-mediated inflammation was visualized in NIID patients using positron emission tomography, correlating with levels of white-matter atrophy. Furthermore, microglia ablation ameliorated neurodegenerative phenotypes and transcriptional alterations in uN2CpolyG-expressing mice but did not affect polyG inclusions. Together, these results demonstrate that polyG is crucial for the pathogenesis of NIID and highlight the significant role of microglia in polyG-induced neurodegeneration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02776-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987141","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: 10.1007/s00401-024-02782-2
Anat O. Stemmer-Rachamimov, Liana Kozanno, Scott R. Plotkin, Justin T. Jordan, Joseph F. Rizzo 3rd
{"title":"Reply to L. Lucchino et al. on commentary on “Histologic correlates of “Choroidal Abnormalities” in Neurofibromatosis type 1”","authors":"Anat O. Stemmer-Rachamimov, Liana Kozanno, Scott R. Plotkin, Justin T. Jordan, Joseph F. Rizzo 3rd","doi":"10.1007/s00401-024-02782-2","DOIUrl":"10.1007/s00401-024-02782-2","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":null,"pages":null},"PeriodicalIF":9.3,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02782-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987142","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}