Pub Date : 2024-06-11DOI: 10.1186/s13024-024-00738-4
Yuan Yuan, Huizhong Li, Kashyap Sreeram, Tuyana Malankhanova, Ravindra Boddu, Samuel Strader, Allison Chang, Nicole Bryant, Talene A. Yacoubian, David G. Standaert, Madalynn Erb, Darren J. Moore, Laurie H. Sanders, Michael W. Lutz, Dmitry Velmeshev, Andrew B. West
LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson’s disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation. The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.
{"title":"Single molecule array measures of LRRK2 kinase activity in serum link Parkinson’s disease severity to peripheral inflammation","authors":"Yuan Yuan, Huizhong Li, Kashyap Sreeram, Tuyana Malankhanova, Ravindra Boddu, Samuel Strader, Allison Chang, Nicole Bryant, Talene A. Yacoubian, David G. Standaert, Madalynn Erb, Darren J. Moore, Laurie H. Sanders, Michael W. Lutz, Dmitry Velmeshev, Andrew B. West","doi":"10.1186/s13024-024-00738-4","DOIUrl":"https://doi.org/10.1186/s13024-024-00738-4","url":null,"abstract":"LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson’s disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation. The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"68 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304393","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 : 2024-06-11DOI: 10.1186/s13024-024-00737-5
Sonia Vazquez-Sanchez, Britt Tilkin, Fatima Gasset-Rosa, Sitao Zhang, Diana Piol, Melissa McAlonis-Downes, Jonathan Artates, Noe Govea-Perez, Yana Verresen, Lin Guo, Don W. Cleveland, James Shorter, Sandrine Da Cruz
RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.
{"title":"Frontotemporal dementia-like disease progression elicited by seeded aggregation and spread of FUS","authors":"Sonia Vazquez-Sanchez, Britt Tilkin, Fatima Gasset-Rosa, Sitao Zhang, Diana Piol, Melissa McAlonis-Downes, Jonathan Artates, Noe Govea-Perez, Yana Verresen, Lin Guo, Don W. Cleveland, James Shorter, Sandrine Da Cruz","doi":"10.1186/s13024-024-00737-5","DOIUrl":"https://doi.org/10.1186/s13024-024-00737-5","url":null,"abstract":"RNA binding proteins have emerged as central players in the mechanisms of many neurodegenerative diseases. In particular, a proteinopathy of fused in sarcoma (FUS) is present in some instances of familial Amyotrophic lateral sclerosis (ALS) and about 10% of sporadic Frontotemporal lobar degeneration (FTLD). Here we establish that focal injection of sonicated human FUS fibrils into brains of mice in which ALS-linked mutant or wild-type human FUS replaces endogenous mouse FUS is sufficient to induce focal cytoplasmic mislocalization and aggregation of mutant and wild-type FUS which with time spreads to distal regions of the brain. Human FUS fibril-induced FUS aggregation in the mouse brain of humanized FUS mice is accelerated by an ALS-causing FUS mutant relative to wild-type human FUS. Injection of sonicated human FUS fibrils does not induce FUS aggregation and subsequent spreading after injection into naïve mouse brains containing only mouse FUS, indicating a species barrier to human FUS aggregation and its prion-like spread. Fibril-induced human FUS aggregates recapitulate pathological features of FTLD including increased detergent insolubility of FUS and TAF15 and amyloid-like, cytoplasmic deposits of FUS that accumulate ubiquitin and p62, but not TDP-43. Finally, injection of sonicated FUS fibrils is shown to exacerbate age-dependent cognitive and behavioral deficits from mutant human FUS expression. Thus, focal seeded aggregation of FUS and further propagation through prion-like spread elicits FUS-proteinopathy and FTLD-like disease progression.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"30 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141304398","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 : 2024-06-09DOI: 10.1186/s13024-024-00732-w
Rogger P Carmen-Orozco, William Tsao, Yingzhi Ye, Irika R Sinha, Koping Chang, Vickie T Trinh, William Chung, Kyra Bowden, Juan C Troncoso, Seth Blackshaw, Lindsey R Hayes, Shuying Sun, Philip C Wong, Jonathan P Ling
Background: Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems.
Methods: We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease.
Results: Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43.
Conclusions: Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.
{"title":"Elevated nuclear TDP-43 induces constitutive exon skipping.","authors":"Rogger P Carmen-Orozco, William Tsao, Yingzhi Ye, Irika R Sinha, Koping Chang, Vickie T Trinh, William Chung, Kyra Bowden, Juan C Troncoso, Seth Blackshaw, Lindsey R Hayes, Shuying Sun, Philip C Wong, Jonathan P Ling","doi":"10.1186/s13024-024-00732-w","DOIUrl":"10.1186/s13024-024-00732-w","url":null,"abstract":"<p><strong>Background: </strong>Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems.</p><p><strong>Methods: </strong>We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease.</p><p><strong>Results: </strong>Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43.</p><p><strong>Conclusions: </strong>Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"45"},"PeriodicalIF":14.9,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11163724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296414","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 : 2024-05-31DOI: 10.1186/s13024-024-00730-y
Yixiang Jiang, Yan Lin, Amber M Tetlow, Ruimin Pan, Changyi Ji, Xiang-Peng Kong, Erin E Congdon, Einar M Sigurdsson
Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.
{"title":"Single-domain antibody-based protein degrader for synucleinopathies.","authors":"Yixiang Jiang, Yan Lin, Amber M Tetlow, Ruimin Pan, Changyi Ji, Xiang-Peng Kong, Erin E Congdon, Einar M Sigurdsson","doi":"10.1186/s13024-024-00730-y","DOIUrl":"10.1186/s13024-024-00730-y","url":null,"abstract":"<p><p>Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4<sup>CRBN</sup>, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"44"},"PeriodicalIF":15.1,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11140919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180306","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 : 2024-05-29DOI: 10.1186/s13024-024-00731-x
Chiara Pedicone, Sarah A. Weitzman, Alan E. Renton, Alison M. Goate
A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases.
{"title":"Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases","authors":"Chiara Pedicone, Sarah A. Weitzman, Alan E. Renton, Alison M. Goate","doi":"10.1186/s13024-024-00731-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00731-x","url":null,"abstract":"A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165177","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 : 2024-05-27DOI: 10.1186/s13024-024-00734-8
Ghazaleh Eskandari-Sedighi, Madeline Crichton, Sameera Zia, Erik Gomez-Cardona, Leonardo M. Cortez, Zain H. Patel, Kei Takahashi-Yamashiro, Chris D. St. Laurent, Gaurav Sidhu, Susmita Sarkar, Vivian Aghanya, Valerie L. Sim, Qiumin Tan, Olivier Julien, Jason R. Plemel, Matthew S. Macauley
Microglia play diverse pathophysiological roles in Alzheimer’s disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.
{"title":"Alzheimer’s disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice","authors":"Ghazaleh Eskandari-Sedighi, Madeline Crichton, Sameera Zia, Erik Gomez-Cardona, Leonardo M. Cortez, Zain H. Patel, Kei Takahashi-Yamashiro, Chris D. St. Laurent, Gaurav Sidhu, Susmita Sarkar, Vivian Aghanya, Valerie L. Sim, Qiumin Tan, Olivier Julien, Jason R. Plemel, Matthew S. Macauley","doi":"10.1186/s13024-024-00734-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00734-8","url":null,"abstract":"Microglia play diverse pathophysiological roles in Alzheimer’s disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"78 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156656","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 : 2024-05-18DOI: 10.1186/s13024-024-00727-7
Rebecca L. Winfree, Emma Nolan, Logan Dumitrescu, Kaj Blennow, Henrik Zetterberg, Katherine A. Gifford, Kimberly R. Pechman, Mabel Seto, Vladislav A. Petyuk, Yanling Wang, Julie Schneider, David A. Bennett, Angela L. Jefferson, Timothy J. Hohman
Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ40, worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ40 (β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ1-38, β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.
{"title":"Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology","authors":"Rebecca L. Winfree, Emma Nolan, Logan Dumitrescu, Kaj Blennow, Henrik Zetterberg, Katherine A. Gifford, Kimberly R. Pechman, Mabel Seto, Vladislav A. Petyuk, Yanling Wang, Julie Schneider, David A. Bennett, Angela L. Jefferson, Timothy J. Hohman","doi":"10.1186/s13024-024-00727-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00727-7","url":null,"abstract":"Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ40, worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ40 (β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ1-38, β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953850","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 : 2024-05-15DOI: 10.1186/s13024-024-00711-1
Xuemei Zeng, Yijun Chen, Anuradha Sehrawat, Jihui Lee, Tara K. Lafferty, Julia Kofler, Sarah B. Berman, Robert A. Sweet, Dana L. Tudorascu, William E. Klunk, Milos D. Ikonomovic, Anna Pfister, Henrik Zetterberg, Beth E. Snitz, Anne D. Cohen, Victor L. Villemagne, Tharick A. Pascoal, M. llyas Kamboh, Oscar I. Lopez, Kaj Blennow, Thomas K. Karikari
Alzheimer’s disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies.
阿尔茨海默病（AD）是最常见的痴呆症，尽管经过数十年的研究和临床调查，但对它的理解和治疗仍然具有挑战性。造成这种情况的部分原因可能是缺乏广泛可用且具有成本效益的诊断和预后方法。最近，在技术进步的推动下，基于血液的注意力缺失症生物标志物领域取得了重大进展，主要是提高了分析灵敏度和测定平台的精确度。一些基于血液的生物标志物已显示出准确检测注意力缺失症病理生理学的巨大潜力。因此，人们对将这些生物标志物用于诊断和预后、作为替代指标用于研究各种协变量对注意力缺失症病理生理学的影响以及加速注意力缺失症治疗试验和监测治疗效果产生了浓厚的兴趣。然而，血液样本的采集、处理、储存、分析和报告方式缺乏标准化，会影响这些生物标记测量的可重复性，从而可能阻碍其在临床和研究环境中的广泛应用。为了帮助解决这些问题，我们根据最近关于样本处理对血液生物标记物测量影响的研究成果，提供了基本的指导原则。这些指南涵盖了包括研究设计、血液采集、血液处理、生物库、生物标记物测量和结果报告在内的重要注意事项。此外，建议指南还包括基因和核糖核酸分析中适当血液处理程序的最佳实践。虽然我们重点关注 AT(N) 标准的主要血液 AD 生物标记物（如淀粉样β [Aβ]40、Aβ42、Aβ42/40 比值、总 tau、磷酸化 tau、神经丝轻链、脑源 tau 和神经胶质纤维酸性蛋白），但我们预计这些指南将普遍适用于其他类型的血液生物标记物。我们还预计，这些指南将有助于研究人员规划和执行生物标记物研究，从而统一样本处理方法，提高各项研究的可比性。
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Pub Date : 2024-04-29DOI: 10.1186/s13024-024-00729-5
Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Walter Gulisano, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Luciano D’Adamio, Shi-Xian Deng, Daniela Puzzo, Ottavio Arancio, Jole Fiorito
<p><b>Correction: Molecular Neurodegeneration (2019) 14:26</b></p><p><b>https://doi.org/10.1186/s13024-019-0326-4</b>.</p><p>After publication of this work, the authors noted that the tubulin and t-CREB bands in panel B and F were similar. This was due to errors in the panels which likely occurred at the time of assembling the figure during the preparation of the manuscript. After carefully going back to all the raw data and checking the 32 bands assembled in the figure, the authors found and selected exact and correct tubulin and t-CREB bands for both panels, thus correcting the image. The errors only pertain to the incorrect representative images in panels B and F and do not affect any of the analyses or conclusions presented in the paper.</p><figure><picture><img alt="figure a" aria-describedby="Figa" height="1286" loading="lazy" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00729-5/MediaObjects/13024_2024_729_Fig1_HTML.png" width="685"/></picture></figure><span>Author notes</span><ol><li><p>Erica Acquarone, Elentina K. Argyrousi and Manon van den Berg contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12- 420D, New York, NY, 10032, USA</p><p>Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Ottavio Arancio & Jole Fiorito</p></li><li><p>DiMi Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, 16132, Italy</p><p>Erica Acquarone</p></li><li><p>Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, 6229, Netherlands</p><p>Elentina K. Argyrousi & Manon van den Berg</p></li><li><p>Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125, Italy</p><p>Walter Gulisano & Daniela Puzzo</p></li><li><p>Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, 16132, Italy</p><p>Elisa Calcagno</p></li><li><p>Department of Pharmacology, Physiology and Neuroscience, Rutgers University, Newark, NJ, USA</p><p>Luciano D’Adamio</p></li><li><p>Department of Medicine, Columbia University, New York, NY, 10032, USA</p><p>Shi-Xian Deng & Ottavio Arancio</p></li><li><p>Oasi Research Institute-IRCCS, Troina, 94018, Italy</p><p>Daniela Puzzo</p></li><li><p>Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA</p><p>Ottavio Arancio</p></li><li><p>Department of Life Sciences, New York Institute of Technology, Northern Boulevard, Theobald Science Center, room 425, P.O. Box 8000, Old Westbury, NY, 11568, USA</p><p>Jole Fiorito</p></li></ol><span>Authors</span><ol><li><span>Erica Acquarone</span>View author publications<p>You can also search for this author in <span>PubMed<span> <
更正：Molecular Neurodegeneration (2019) 14:26https://doi.org/10.1186/s13024-019-0326-4.After 在发表这项工作时，作者注意到 B 组和 F 组中的微管蛋白和 t-CREB 条带相似。这是由于图板中的错误造成的，而这些错误很可能是在准备稿件期间拼图时出现的。作者仔细查阅了所有原始数据并检查了图中的 32 条带，为两个面板找到并选择了准确和正确的微管蛋白和 t-CREB 带，从而纠正了图像。作者简介Erica Acquarone、Elentina K. Argyrousi 和 Manon van den Berg 对本研究做出了同样的贡献。作者和工作单位阿尔茨海默病和大脑老化研究所，630 West 168th Street, P&S 12- 420D, New York, NY, 10032, USAErica Acquarone、Elentina K. Argyrousi 和 Manon van den Berg 对本研究做出了同样的贡献。Argyrousi, Manon van den Berg, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Ottavio Arancio & Jole FioritoDiMi 系内科和医学专科，热那亚大学，热那亚，16132，意大利Erica Acquarone心理学和神经科学学院，马斯特里赫特大学，马斯特里赫特，6229，荷兰Elentina K.Argyrousi & Manon van den BergDepartment of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125, ItalyWalter Gulisano &；Daniela PuzzoDepartment of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, 16132, ItalyElisa CalcagnoDepartment of Pharmacology, Physiology and Neuroscience, Rutgers University, Newark, NJ, USALuciano D'AdamioDepartment of Medicine, Columbia University, New York, NY, 10032, USAShiXian Deng &；Ottavio ArancioOasi Research Institute-IRCCS, Troina, 94018, ItalyDaniela PuzzoDepartment of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USAOttavio ArancioDepartment of Life Sciences, New York Institute of Technology, Northern Boulevard, Theobald Science Center, room 425, P. O. Box 8000, Old Westwood.O. Box 8000, Old Westbury, NY, 11568, USAJole Fiorito作者Erica Acquarone查看作者发表的文章您也可以在PubMed Google ScholarElentina K. Argyrousi中搜索该作者。ArgyrousiView 作者发表作品您也可以在 PubMed Google ScholarManon van den BergView 作者发表作品您也可以在 PubMed Google ScholarWalter GulisanoView 作者发表作品您也可以在 PubMed Google ScholarMauro FàView 作者发表作品您也可以在 PubMed Google ScholarAgnieszkaStaniszewskiView 作者发表作品您也可以在 PubMed Google ScholarElisa CalcagnoView 作者发表作品您也可以在 PubMed Google ScholarElisa ZuccarelloView 作者发表作品您也可以在 PubMed Google ScholarLuciano D'AdamioView 作者发表作品您也可以在 PubMed Google ScholarShi-Xian Deng查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Daniela Puzzo查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Ottavio Arancio查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Jole Fiorito查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者通信作者Ottavio Arancio或Jole Fiorito。出版者注Springer Nature对已出版地图中的管辖权主张和机构隶属关系保持中立。原文的在线版本可在以下网址找到：https://doi.org/10.1186/s13024-019-0326-4.Open Access 本文采用知识共享署名 4.0 国际许可协议进行许可，该协议允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出许可使用范围，则您需要直接从版权所有者处获得许可。要查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的贷方行另有说明，否则知识共享公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载和许可引用本文Acquarone, E. , Argyrousi, E.K., van den Berg, M. et al. Correction：一氧化氮级联上调可缓解tau寡聚体诱导的突触和记忆功能障碍。Mol Neurodegenerat
{"title":"Correction: Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade","authors":"Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Walter Gulisano, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Luciano D’Adamio, Shi-Xian Deng, Daniela Puzzo, Ottavio Arancio, Jole Fiorito","doi":"10.1186/s13024-024-00729-5","DOIUrl":"https://doi.org/10.1186/s13024-024-00729-5","url":null,"abstract":"<p><b>Correction: Molecular Neurodegeneration (2019) 14:26</b></p><p><b>https://doi.org/10.1186/s13024-019-0326-4</b>.</p><p>After publication of this work, the authors noted that the tubulin and t-CREB bands in panel B and F were similar. This was due to errors in the panels which likely occurred at the time of assembling the figure during the preparation of the manuscript. After carefully going back to all the raw data and checking the 32 bands assembled in the figure, the authors found and selected exact and correct tubulin and t-CREB bands for both panels, thus correcting the image. The errors only pertain to the incorrect representative images in panels B and F and do not affect any of the analyses or conclusions presented in the paper.</p><figure><picture><img alt=\"figure a\" aria-describedby=\"Figa\" height=\"1286\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00729-5/MediaObjects/13024_2024_729_Fig1_HTML.png\" width=\"685\"/></picture></figure><span>Author notes</span><ol><li><p>Erica Acquarone, Elentina K. Argyrousi and Manon van den Berg contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12- 420D, New York, NY, 10032, USA</p><p>Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Ottavio Arancio & Jole Fiorito</p></li><li><p>DiMi Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, 16132, Italy</p><p>Erica Acquarone</p></li><li><p>Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, 6229, Netherlands</p><p>Elentina K. Argyrousi & Manon van den Berg</p></li><li><p>Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125, Italy</p><p>Walter Gulisano & Daniela Puzzo</p></li><li><p>Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, 16132, Italy</p><p>Elisa Calcagno</p></li><li><p>Department of Pharmacology, Physiology and Neuroscience, Rutgers University, Newark, NJ, USA</p><p>Luciano D’Adamio</p></li><li><p>Department of Medicine, Columbia University, New York, NY, 10032, USA</p><p>Shi-Xian Deng & Ottavio Arancio</p></li><li><p>Oasi Research Institute-IRCCS, Troina, 94018, Italy</p><p>Daniela Puzzo</p></li><li><p>Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA</p><p>Ottavio Arancio</p></li><li><p>Department of Life Sciences, New York Institute of Technology, Northern Boulevard, Theobald Science Center, room 425, P.O. Box 8000, Old Westbury, NY, 11568, USA</p><p>Jole Fiorito</p></li></ol><span>Authors</span><ol><li><span>Erica Acquarone</span>View author publications<p>You can also search for this author in <span>PubMed<span> <","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"30 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814617","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 : 2024-04-24DOI: 10.1186/s13024-024-00725-9
Lina Vandermeulen, Ivana Geric, Laura Fumagalli, Mohamed Kreir, Ashley Lu, Annelies Nonneman, Jessie Premereur, Leen Wolfs, Rafaela Policarpo, Nicola Fattorelli, An De Bondt, Ilse Van Den Wyngaert, Bob Asselbergh, Mark Fiers, Bart De Strooper, Constantin d’Ydewalle, Renzo Mancuso
Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo. We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-β plaques in vivo in a model of AD. This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo.
小胶质细胞在维持大脑稳态和神经变性方面发挥着重要作用。载脂蛋白 E（APOE）和髓样细胞上表达的触发受体 2（TREM2）等主要或专门在髓样细胞中表达的基因的遗传变异被发现是阿尔茨海默病（AD）的最强风险因素，这凸显了小胶质细胞生物学在大脑中的重要性。几种小胶质细胞蛋白的序列、结构和功能在不同物种间的一致性很差，这阻碍了旨在调节特定小胶质细胞基因表达的策略的开发。针对 APOE 和 TREM2 的一种方法是使用反义寡核苷酸（ASO）来调节它们的表达。在这项研究中，我们发现、生产并测试了针对人类 APOE 和 TREM2 的新型、选择性和强效 ASO。我们结合使用了体外 iPSC-小胶质细胞模型以及小胶质细胞异种移植小鼠，以证明其在体内人类小胶质细胞中的活性。我们证明了它们在体外人类 iPSC 小胶质细胞中的疗效，以及在异种移植小胶质细胞模型中的体内药理活性。我们证明了以人类小胶质细胞为靶点的 ASOs 可以改变它们的转录谱，以及它们在体内 AD 模型中对淀粉样蛋白-β 斑块的反应。这项研究首次证明了人类小胶质细胞可以通过 ASOs 以剂量依赖的方式进行调节，从而操纵体内小胶质细胞的表型和对神经变性的反应。
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