Acta Neuropathologica最新文献

{"title":"Mutations in ARHGEF15 cause autosomal dominant hereditary cerebral small vessel disease and osteoporotic fracture","authors":"Xuebing Ding,&nbsp;Yongkang Chen,&nbsp;Cancan Guo,&nbsp;Yu Fu,&nbsp;Chi Qin,&nbsp;Qingyong Zhu,&nbsp;Jiuqi Wang,&nbsp;Rui Zhang,&nbsp;Haiyan Tian,&nbsp;Renyi Feng,&nbsp;Han Liu,&nbsp;Dongxiao Liang,&nbsp;Guanghui Wang,&nbsp;Junfang Teng,&nbsp;Jinchen Li,&nbsp;Beisha Tang,&nbsp;Xuejing Wang","doi":"10.1007/s00401-023-02560-6","DOIUrl":"10.1007/s00401-023-02560-6","url":null,"abstract":"<div><p>Cerebral small vessel disease (CSVD) is a prominent cause of ischemic and hemorrhagic stroke and a leading cause of vascular dementia, affecting small penetrating vessels of the brain. Despite current advances in genetic susceptibility studies, challenges remain in defining the causative genes and the underlying pathophysiological mechanisms. Here, we reported that the <i>ARHGEF15</i> gene was a causal gene linked to autosomal dominant inherited CSVD. We identified one heterozygous nonsynonymous mutation of the <i>ARHGEF15</i> gene that cosegregated completely in two families with CSVD, and a heterozygous nonsynonymous mutation and a stop-gain mutation in two individuals with sporadic CSVD, respectively. Intriguingly, clinical imaging and pathological findings displayed severe osteoporosis and even osteoporotic fractures in all the <i>ARHGEF15</i> mutation carriers. In vitro experiments indicated that <i>ARHGEF15</i> mutations resulted in RhoA/ROCK2 inactivation-induced F-actin cytoskeleton disorganization in vascular smooth muscle cells and endothelial cells and osteoblast dysfunction by inhibiting the Wnt/β-catenin signaling pathway in osteoblast cells. Furthermore, Arhgef15-e(V368M)1 transgenic mice developed CSVD-like pathological and behavioral phenotypes, accompanied by severe osteoporosis. Taken together, our findings provide strong evidence that loss-of-function mutations of the <i>ARHGEF15</i> gene cause CSVD accompanied by osteoporotic fracture.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 5","pages":"681 - 705"},"PeriodicalIF":12.7,"publicationDate":"2023-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02560-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9347861","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}

{"title":"A point mutation in GPI-attachment signal peptide accelerates the development of prion disease","authors":"Atsushi Kobayashi,&nbsp;Tetsuya Hirata,&nbsp;Taishi Shimazaki,&nbsp;Yoshiko Munesue,&nbsp;Keisuke Aoshima,&nbsp;Takashi Kimura,&nbsp;Junko Nio-Kobayashi,&nbsp;Rie Hasebe,&nbsp;Atsuko Takeuchi,&nbsp;Yuichi Matsuura,&nbsp;Satoshi Kusumi,&nbsp;Daisuke Koga,&nbsp;Yasushi Iwasaki,&nbsp;Taroh Kinoshita,&nbsp;Shirou Mohri,&nbsp;Tetsuyuki Kitamoto","doi":"10.1007/s00401-023-02553-5","DOIUrl":"10.1007/s00401-023-02553-5","url":null,"abstract":"<div><p>A missense variant from methionine to arginine at codon 232 (M232R) of the prion protein gene accounts for ~ 15% of Japanese patients with genetic prion diseases. However, pathogenic roles of the M232R substitution for the induction of prion disease have remained elusive because family history is usually absent in patients with M232R. In addition, the clinicopathologic phenotypes of patients with M232R are indistinguishable from those of sporadic Creutzfeldt-Jakob disease patients. Furthermore, the M232R substitution is located in the glycosylphosphatidylinositol (GPI)-attachment signal peptide that is cleaved off during the maturation of prion proteins. Therefore, there has been an argument that the M232R substitution might be an uncommon polymorphism rather than a pathogenic mutation. To unveil the role of the M232R substitution in the GPI-attachment signal peptide of prion protein in the pathogenesis of prion disease, here we generated a mouse model expressing human prion proteins with M232R and investigated the susceptibility to prion disease. The M232R substitution accelerates the development of prion disease in a prion strain-dependent manner, without affecting prion strain-specific histopathologic and biochemical features. The M232R substitution did not alter the attachment of GPI nor GPI-attachment site. Instead, the substitution altered endoplasmic reticulum translocation pathway of prion proteins by reducing the hydrophobicity of the GPI-attachment signal peptide, resulting in the reduction of <i>N</i>-linked glycosylation and GPI glycosylation of prion proteins. To the best of our knowledge, this is the first time to show a direct relationship between a point mutation in the GPI-attachment signal peptide and the development of disease.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 5","pages":"637 - 650"},"PeriodicalIF":12.7,"publicationDate":"2023-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10322399","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}

{"title":"IL-10-providing B cells govern pro-inflammatory activity of macrophages and microglia in CNS autoimmunity","authors":"Anastasia Geladaris,&nbsp;Silke Häusser-Kinzel,&nbsp;Roxanne Pretzsch,&nbsp;Nitzan Nissimov,&nbsp;Klaus Lehmann-Horn,&nbsp;Darius Häusler,&nbsp;Martin S. Weber","doi":"10.1007/s00401-023-02552-6","DOIUrl":"10.1007/s00401-023-02552-6","url":null,"abstract":"<div><p>B cells contribute to chronic inflammatory conditions as source of antibody-secreting plasma cells and as antigen-presenting cells activating T cells, making anti-CD20-mediated B cell depletion a widely used therapeutic option. B cells or B cell subsets may, however, exert regulatory effects, while to date, the immunological and/or clinical impact of these observations remained unclear. We found that in multiple sclerosis (MS) patients, B cells contain regulatory features and that their removal enhanced activity of monocytes. Using a co-culture system, we identified B cell-provided interleukin (IL)-10 as key factor in controlling pro-inflammatory activity of peripheral myeloid cells as well as microglia. Depleting B cells via anti-CD20 in a mouse model of MS unleashed the activity of myeloid cells and microglia and accelerated disease severity; in contrast, adoptive transfer of IL-10-providing B cells restored in vivo control of central nervous system (CNS) macrophages and microglia and reversed clinical exacerbation. These findings suggest that B cells exert meaningful regulatory properties, which should be considered when designing novel B cell-directed agents.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"461 - 477"},"PeriodicalIF":12.7,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02552-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9322002","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}

{"title":"New SNCA mutation and structures of α-synuclein filaments from juvenile-onset synucleinopathy","authors":"Yang Yang,&nbsp;Holly J. Garringer,&nbsp;Yang Shi,&nbsp;Sofia Lövestam,&nbsp;Sew Peak-Chew,&nbsp;Xianjun Zhang,&nbsp;Abhay Kotecha,&nbsp;Mehtap Bacioglu,&nbsp;Atsuo Koto,&nbsp;Masaki Takao,&nbsp;Maria Grazia Spillantini,&nbsp;Bernardino Ghetti,&nbsp;Ruben Vidal,&nbsp;Alexey G. Murzin,&nbsp;Sjors H. W. Scheres,&nbsp;Michel Goedert","doi":"10.1007/s00401-023-02550-8","DOIUrl":"10.1007/s00401-023-02550-8","url":null,"abstract":"<div><p>A 21-nucleotide duplication in one allele of <i>SNCA</i> was identified in a previously described disease with abundant α-synuclein inclusions that we now call juvenile-onset synucleinopathy (JOS). This mutation translates into the insertion of MAAAEKT after residue 22 of α-synuclein, resulting in a protein of 147 amino acids. Both wild-type and mutant proteins were present in sarkosyl-insoluble material that was extracted from frontal cortex of the individual with JOS and examined by electron cryo-microscopy. The structures of JOS filaments, comprising either a single protofilament, or a pair of protofilaments, revealed a new α-synuclein fold that differs from the folds of Lewy body diseases and multiple system atrophy (MSA). The JOS fold consists of a compact core, the sequence of which (residues 36–100 of wild-type α-synuclein) is unaffected by the mutation, and two disconnected density islands (A and B) of mixed sequences. There is a non-proteinaceous cofactor bound between the core and island A. The JOS fold resembles the common substructure of MSA Type I and Type II dimeric filaments, with its core segment approximating the C-terminal body of MSA protofilaments B and its islands mimicking the N-terminal arm of MSA protofilaments A. The partial similarity of JOS and MSA folds extends to the locations of their cofactor-binding sites. In vitro assembly of recombinant wild-type α-synuclein, its insertion mutant and their mixture yielded structures that were distinct from those of JOS filaments. Our findings provide insight into a possible mechanism of JOS fibrillation in which mutant α-synuclein of 147 amino acids forms a nucleus with the JOS fold, around which wild-type and mutant proteins assemble during elongation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 5","pages":"561 - 572"},"PeriodicalIF":12.7,"publicationDate":"2023-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02550-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9335414","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}

{"title":"Variants in DTNA cause a mild, dominantly inherited muscular dystrophy","authors":"Andres Nascimento,&nbsp;Christine C. Bruels,&nbsp;Sandra Donkervoort,&nbsp;A. Reghan Foley,&nbsp;Anna Codina,&nbsp;Jose C. Milisenda,&nbsp;Elicia A. Estrella,&nbsp;Chengcheng Li,&nbsp;Jordi Pijuan,&nbsp;Isabelle Draper,&nbsp;Ying Hu,&nbsp;Seth A. Stafki,&nbsp;Lynn S. Pais,&nbsp;Vijay S. Ganesh,&nbsp;Anne O’Donnell-Luria,&nbsp;Safoora B. Syeda,&nbsp;Laura Carrera-García,&nbsp;Jessica Expósito-Escudero,&nbsp;Delia Yubero,&nbsp;Loreto Martorell,&nbsp;Iago Pinal-Fernandez,&nbsp;Hart G. W. Lidov,&nbsp;Andrew L. Mammen,&nbsp;Josep M. Grau-Junyent,&nbsp;Carlos Ortez,&nbsp;Francesc Palau,&nbsp;Partha S. Ghosh,&nbsp;Basil T. Darras,&nbsp;Cristina Jou,&nbsp;Louis M. Kunkel,&nbsp;Janet Hoenicka,&nbsp;Carsten G. Bönnemann,&nbsp;Peter B. Kang,&nbsp;Daniel Natera-de Benito","doi":"10.1007/s00401-023-02551-7","DOIUrl":"10.1007/s00401-023-02551-7","url":null,"abstract":"<div><p><i>DTNA</i> encodes α-dystrobrevin, a component of the macromolecular dystrophin–glycoprotein complex (DGC) that binds to dystrophin/utrophin and α-syntrophin. Mice lacking α-dystrobrevin have a muscular dystrophy phenotype, but variants in <i>DTNA</i> have not previously been associated with human skeletal muscle disease. We present 12 individuals from four unrelated families with two different monoallelic <i>DTNA</i> variants affecting the coiled-coil domain of α-dystrobrevin. The five affected individuals from family A harbor a c.1585G &gt; A; p.Glu529Lys variant, while the recurrent c.1567_1587del; p.Gln523_Glu529del <i>DTNA</i> variant was identified in the other three families (family B: four affected individuals, family C: one affected individual, and family D: two affected individuals). Myalgia and exercise intolerance, with variable ages of onset, were reported in 10 of 12 affected individuals. Proximal lower limb weakness with onset in the first decade of life was noted in three individuals. Persistent elevations of serum creatine kinase (CK) levels were detected in 11 of 12 affected individuals, 1 of whom had an episode of rhabdomyolysis at 20 years of age. Autism spectrum disorder or learning disabilities were reported in four individuals with the c.1567_1587 deletion. Muscle biopsies in eight affected individuals showed mixed myopathic and dystrophic findings, characterized by fiber size variability, internalized nuclei, and slightly increased extracellular connective tissue and inflammation. Immunofluorescence analysis of biopsies from five affected individuals showed reduced α-dystrobrevin immunoreactivity and variably reduced immunoreactivity of other DGC proteins: dystrophin, α, β, δ and γ-sarcoglycans, and α and β-dystroglycans. The <i>DTNA</i> deletion disrupted an interaction between α-dystrobrevin and syntrophin. Specific variants in the coiled-coil domain of <i>DTNA</i> cause skeletal muscle disease with variable penetrance. Affected individuals show a spectrum of clinical manifestations, with severity ranging from hyperCKemia, myalgias, and exercise intolerance to childhood-onset proximal muscle weakness. Our findings expand the molecular etiologies of both muscular dystrophy and paucisymptomatic hyperCKemia, to now include monoallelic <i>DTNA</i> variants as a novel cause of skeletal muscle disease in humans.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"479 - 496"},"PeriodicalIF":12.7,"publicationDate":"2023-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10554885","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}

{"title":"Correction to: Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease","authors":"Antonio Boza-Serrano,&nbsp;Rocío Ruiz,&nbsp;Raquel Sanchez-Varo,&nbsp;Juan García-Revilla,&nbsp;Yiyi Yang,&nbsp;Itzia Jimenez-Ferrer,&nbsp;Agnes Paulus,&nbsp;Malin Wennström,&nbsp;Anna Vilalta,&nbsp;David Allendorf,&nbsp;Jose Carlos Davila,&nbsp;John Stegmayr,&nbsp;Sebastian Jiménez,&nbsp;Maria A. Roca-Ceballos,&nbsp;Victoria Navarro-Garrido,&nbsp;Maria Swanberg,&nbsp;Christine L. Hsieh,&nbsp;Luis M. Real,&nbsp;Elisabet Englund,&nbsp;Sara Linse,&nbsp;Hakon Leffler,&nbsp;Ulf J. Nilsson,&nbsp;Guy C. Brown,&nbsp;Antonia Gutierrez,&nbsp;Javier Vitorica,&nbsp;Jose Luis Venero,&nbsp;Tomas Deierborg","doi":"10.1007/s00401-023-02549-1","DOIUrl":"10.1007/s00401-023-02549-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"509 - 510"},"PeriodicalIF":12.7,"publicationDate":"2023-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02549-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9490869","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}

{"title":"SMARCA4-associated schwannomatosis","authors":"Fiona Chan-Pak-Choon,&nbsp;Carla Roca,&nbsp;Anne-Sophie Chong,&nbsp;Clara Nogué,&nbsp;Sonja Dahlum,&nbsp;Rachel Austin,&nbsp;Helen Mar Fan,&nbsp;Karin Y. van Spaendonck-Zwarts,&nbsp;Neil K. Lambie,&nbsp;Thomas Robertson,&nbsp;Reiner Siebert,&nbsp;Barbara Rivera,&nbsp;William D. Foulkes","doi":"10.1007/s00401-023-02546-4","DOIUrl":"10.1007/s00401-023-02546-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"505 - 507"},"PeriodicalIF":12.7,"publicationDate":"2023-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9267848","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}

{"title":"Correction to: Amplification of the PLAG-family genes—PLAGL1 and PLAGL2—is a key feature of the novel tumor type CNS embryonal tumor with PLAGL amplification","authors":"Michaela-Kristina Keck,&nbsp;Martin Sill,&nbsp;Andrea Wittmann,&nbsp;Piyush Joshi,&nbsp;Damian Stichel,&nbsp;Pengbo Beck,&nbsp;Konstantin Okonechnikow,&nbsp;Philipp Sievers,&nbsp;Annika K. Wefers,&nbsp;Federico Roncaroli,&nbsp;Shivaram Avula,&nbsp;Martin G. McCabe,&nbsp;James T. Hayden,&nbsp;Pieter Wesseling,&nbsp;Ingrid Øra,&nbsp;Monica Nistér,&nbsp;Mariëtte E. G. Kranendonk,&nbsp;Bastiaan B. J. Tops,&nbsp;Michal Zapotocky,&nbsp;Josef Zamecnik,&nbsp;Alexandre Vasiljevic,&nbsp;Tanguy Fenouil,&nbsp;David Meyronet,&nbsp;Katja von Hoff,&nbsp;Ulrich Schüller,&nbsp;Hugues Loiseau,&nbsp;Dominique Figarella-Branger,&nbsp;Christof M. Kramm,&nbsp;Dominik Sturm,&nbsp;David Scheie,&nbsp;Tuomas Rauramaa,&nbsp;Jouni Pesola,&nbsp;Johannes Gojo,&nbsp;Christine Haberler,&nbsp;Sebastian Brandner,&nbsp;Tom Jacques,&nbsp;Alexandra Sexton Oates,&nbsp;Richard Saffery,&nbsp;Ewa Koscielniak,&nbsp;Suzanne J. Baker,&nbsp;Stephen Yip,&nbsp;Matija Snuderl,&nbsp;Nasir Ud Din,&nbsp;David Samuel,&nbsp;Kathrin Schramm,&nbsp;Mirjam Blattner-Johnson,&nbsp;Florian Selt,&nbsp;Jonas Ecker,&nbsp;Till Milde,&nbsp;Andreas von Deimling,&nbsp;Andrey Korshunov,&nbsp;Arie Perry,&nbsp;Stefan M. Pfister,&nbsp;Felix Sahm,&nbsp;David A. Solomon,&nbsp;David T. W. Jones","doi":"10.1007/s00401-023-02538-4","DOIUrl":"10.1007/s00401-023-02538-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"511 - 514"},"PeriodicalIF":12.7,"publicationDate":"2023-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02538-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9135942","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}

{"title":"Retinal pathological features and proteome signatures of Alzheimer’s disease","authors":"Yosef Koronyo,&nbsp;Altan Rentsendorj,&nbsp;Nazanin Mirzaei,&nbsp;Giovanna C. Regis,&nbsp;Julia Sheyn,&nbsp;Haoshen Shi,&nbsp;Ernesto Barron,&nbsp;Galen Cook-Wiens,&nbsp;Anthony R. Rodriguez,&nbsp;Rodrigo Medeiros,&nbsp;Joao A. Paulo,&nbsp;Veer B. Gupta,&nbsp;Andrei A. Kramerov,&nbsp;Alexander V. Ljubimov,&nbsp;Jennifer E. Van Eyk,&nbsp;Stuart L. Graham,&nbsp;Vivek K. Gupta,&nbsp;John M. Ringman,&nbsp;David R. Hinton,&nbsp;Carol A. Miller,&nbsp;Keith L. Black,&nbsp;Antonino Cattaneo,&nbsp;Giovanni Meli,&nbsp;Mehdi Mirzaei,&nbsp;Dieu-Trang Fuchs,&nbsp;Maya Koronyo-Hamaoui","doi":"10.1007/s00401-023-02548-2","DOIUrl":"10.1007/s00401-023-02548-2","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) pathologies were discovered in the accessible neurosensory retina. However, their exact nature and topographical distribution, particularly in the early stages of functional impairment, and how they relate to disease progression in the brain remain largely unknown. To better understand the pathological features of AD in the retina, we conducted an extensive histopathological and biochemical investigation of postmortem retina and brain tissues from 86 human donors. Quantitative examination of superior and inferior temporal retinas from mild cognitive impairment (MCI) and AD patients compared to those with normal cognition (NC) revealed significant increases in amyloid β-protein (Aβ₄₂) forms and novel intraneuronal Aβ oligomers (AβOi), which were closely associated with exacerbated retinal macrogliosis, microgliosis, and tissue atrophy. These pathologies were unevenly distributed across retinal layers and geometrical areas, with the inner layers and peripheral subregions exhibiting most pronounced accumulations in the MCI and AD versus NC retinas. While microgliosis was increased in the retina of these patients, the proportion of microglial cells engaging in Aβ uptake was reduced. Female AD patients exhibited higher levels of retinal microgliosis than males. Notably, retinal Aβ₄₂, S100 calcium-binding protein B⁺ macrogliosis, and atrophy correlated with severity of brain Aβ pathology, tauopathy, and atrophy, and most retinal pathologies reflected Braak staging. All retinal biomarkers correlated with the cognitive scores, with retinal Aβ₄₂, far-peripheral AβOi and microgliosis displaying the strongest correlations. Proteomic analysis of AD retinas revealed activation of specific inflammatory and neurodegenerative processes and inhibition of oxidative phosphorylation/mitochondrial, and photoreceptor-related pathways. This study identifies and maps retinopathy in MCI and AD patients, demonstrating the quantitative relationship with brain pathology and cognition, and may lead to reliable retinal biomarkers for noninvasive retinal screening and monitoring of AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 4","pages":"409 - 438"},"PeriodicalIF":12.7,"publicationDate":"2023-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02548-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9260860","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}

{"title":"Dysregulation of astrocytic Ca2+ signaling and gliotransmitter release in mouse models of α-synucleinopathies","authors":"Carmen Nanclares,&nbsp;Jonah Poynter,&nbsp;Hector A. Martell-Martinez,&nbsp;Scott Vermilyea,&nbsp;Alfonso Araque,&nbsp;Paulo Kofuji,&nbsp;Michael K. Lee,&nbsp;Ana Covelo","doi":"10.1007/s00401-023-02547-3","DOIUrl":"10.1007/s00401-023-02547-3","url":null,"abstract":"<div><p>α-Synuclein is a major component of Lewy bodies (LB) and Lewy neurites (LN) appearing in the postmortem brain of Parkinson's disease (PD) and other α-synucleinopathies. While most studies of α-synucleinopathies have focused on neuronal and synaptic alterations as well as dysfunctions of the astrocytic homeostatic roles, whether the bidirectional astrocyte–neuronal communication is affected in these diseases remains unknown. We have investigated whether the astrocyte Ca²⁺ excitability and the glutamatergic gliotransmission underlying astrocyte–neuronal signaling are altered in several transgenic mouse models related to α-synucleinopathies, i.e., mice expressing high and low levels of the human A53T mutant α-synuclein (G2-3 and H5 mice, respectively) globally or selectively in neurons (iSyn mice), mice expressing human wildtype α-synuclein (I2-2 mice), and mice expressing A30P mutant α-synuclein (O2 mice). Combining astrocytic Ca²⁺ imaging and neuronal electrophysiological recordings in hippocampal slices of these mice, we have found that compared to non-transgenic mice, astrocytes in G2-3 mice at different ages (1–6 months) displayed a Ca²⁺ hyperexcitability that was independent of neurotransmitter receptor activation, suggesting that the expression of α-synuclein mutant A53T altered the intrinsic properties of astrocytes. Similar dysregulation of the astrocyte Ca²⁺ signal was present in H5 mice, but not in I2-2 and O2 mice, indicating α-synuclein mutant-specific effects. Moreover, astrocyte Ca²⁺ hyperexcitability was absent in mice expressing the α-synuclein mutant A53T selectively in neurons, indicating that the effects on astrocytes were cell-autonomous. Consistent with these effects, glutamatergic gliotransmission was enhanced in G2-3 and H5 mice, but was unaffected in I2-2, O2 and iSyn mice. These results indicate a cell-autonomous effect of pathogenic A53T expression in astrocytes that may contribute to the altered neuronal and synaptic function observed in α-synucleinopathies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"145 5","pages":"597 - 610"},"PeriodicalIF":12.7,"publicationDate":"2023-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-023-02547-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"50468134","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}