Molecular Neurodegeneration最新文献

{"title":"Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting","authors":"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","doi":"10.1186/s13024-024-00711-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00711-1","url":null,"abstract":"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.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140924985","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: 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}

{"title":"Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer’s disease","authors":"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","doi":"10.1186/s13024-024-00725-9","DOIUrl":"https://doi.org/10.1186/s13024-024-00725-9","url":null,"abstract":"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.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"304 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640417","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":"Adaptive immune changes associate with clinical progression of Alzheimer’s disease","authors":"Lynn van Olst, Alwin Kamermans, Sem Halters, Susanne M. A. van der Pol, Ernesto Rodriguez, Inge M. W. Verberk, Sanne G. S. Verberk, Danielle W. R. Wessels, Carla Rodriguez-Mogeda, Jan Verhoeff, Dorine Wouters, Jan Van den Bossche, Juan J. Garcia-Vallejo, Afina W. Lemstra, Maarten E. Witte, Wiesje M. van der Flier, Charlotte E. Teunissen, Helga E. de Vries","doi":"10.1186/s13024-024-00726-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00726-8","url":null,"abstract":"Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology. • Peripheral CD8+ TEMRA cells expressing markers associated with senescence accumulate in AD patients before dementia onset. • Peripheral immune cells correlate with AD biomarkers, varying by clinical AD stage. • APOE ε4 modifies peripheral immunity and its association with clinical AD measures.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"43 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642595","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":"Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration","authors":"Asmaa Yehia, Osama A. Abulseoud","doi":"10.1186/s13024-024-00728-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00728-6","url":null,"abstract":"The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"22 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140620293","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":"Gut microbiota-host lipid crosstalk in Alzheimer’s disease: implications for disease progression and therapeutics","authors":"Ya-Xi Luo, Ling-Ling Yang, Xiu-Qing Yao","doi":"10.1186/s13024-024-00720-0","DOIUrl":"https://doi.org/10.1186/s13024-024-00720-0","url":null,"abstract":"Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer’s disease. The role of gut microbiota in Alzheimer’s disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer’s disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer’s disease based on existing data.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"41 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557201","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":"Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity","authors":"Pasquale D’Acunzo, Elentina K. Argyrousi, Jonathan M. Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N. Goulbourne, Ottavio Arancio, Efrat Levy","doi":"10.1186/s13024-024-00721-z","DOIUrl":"https://doi.org/10.1186/s13024-024-00721-z","url":null,"abstract":"Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"66 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553638","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":"The concept of resilience to Alzheimer’s Disease: current definitions and cellular and molecular mechanisms","authors":"Luuk E. de Vries, Inge Huitinga, Helmut W. Kessels, Dick F. Swaab, Joost Verhaagen","doi":"10.1186/s13024-024-00719-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00719-7","url":null,"abstract":"Some individuals are able to maintain their cognitive abilities despite the presence of significant Alzheimer’s Disease (AD) neuropathological changes. This discrepancy between cognition and pathology has been labeled as resilience and has evolved into a widely debated concept. External factors such as cognitive stimulation are associated with resilience to AD, but the exact cellular and molecular underpinnings are not completely understood. In this review, we discuss the current definitions used in the field, highlight the translational approaches used to investigate resilience to AD and summarize the underlying cellular and molecular substrates of resilience that have been derived from human and animal studies, which have received more and more attention in the last few years. From these studies the picture emerges that resilient individuals are different from AD patients in terms of specific pathological species and their cellular reaction to AD pathology, which possibly helps to maintain cognition up to a certain tipping point. Studying these rare resilient individuals can be of great importance as it could pave the way to novel therapeutic avenues for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"32 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140538723","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":"Regulatory T cells limit age-associated retinal inflammation and neurodegeneration","authors":"María Llorián-Salvador, Alerie G. de Fuente, Christopher E. McMurran, Amy Dashwood, James Dooley, Adrian Liston, Rosana Penalva, Yvonne Dombrowski, Alan W. Stitt, Denise C. Fitzgerald","doi":"10.1186/s13024-024-00724-w","DOIUrl":"https://doi.org/10.1186/s13024-024-00724-w","url":null,"abstract":"Ageing is the principal risk factor for retinal degenerative diseases, which are the commonest cause of blindness in the developed countries. These conditions include age-related macular degeneration or diabetic retinopathy. Regulatory T cells play a vital role in immunoregulation of the nervous system by limiting inflammation and tissue damage in health and disease. Because the retina was long-considered an immunoprivileged site, the precise contribution of regulatory T cells in retinal homeostasis and in age-related retinal diseases remains unknown. Regulatory T cells were selectively depleted in both young (2–4 months) and aged (18–23 months) FoxP3-DTR mice. We evaluated neuroretinal degeneration, gliosis, subretinal space phagocyte infiltration, and retinal pigmented epithelium morphology through immunofluorescence analysis. Subsequently, aged Treg depleted animals underwent adoptive transfer of both young and aged regulatory T cells from wild-type mice, and the resulting impact on neurodegeneration was assessed. Statistical analyses employed included the U-Mann Whitney test, and for comparisons involving more than two groups, 1-way ANOVA analysis followed by Bonferroni’s post hoc test. Our study shows that regulatory T cell elimination leads to retinal pigment epithelium cell dysmorphology and accumulation of phagocytes in the subretinal space of young and aged mice. However, only aged mice experience retinal neurodegeneration and gliosis. Surprisingly, adoptive transfer of young but not aged regulatory T cells reverse these changes. Our findings demonstrate an essential role for regulatory T cells in maintaining age retinal homeostasis and preventing age-related neurodegeneration. This previously undescribed role of regulatory T cells in limiting retinal inflammation, RPE/choroid epithelium damage and subsequently photoreceptor loss with age, opens novel avenues to explore regulatory T cell neuroprotective and anti-inflammatory properties as potential therapeutic approaches for age-related retinal diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534179","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":"An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders","authors":"Marie-France Dorion, Diana Casas, Irina Shlaifer, Moein Yaqubi, Peter Fleming, Nathan Karpilovsky, Carol X.-Q. Chen, Michael Nicouleau, Valerio E. C. Piscopo, Emma J. MacDougall, Aeshah Alluli, Taylor M. Goldsmith, Alexandria Schneider, Samuel Dorion, Nathalia Aprahamian, Adam MacDonald, Rhalena A. Thomas, Roy W. R. Dudley, Jeffrey A. Hall, Edward A. Fon, Jack P. Antel, Jo Anne Stratton, Thomas M. Durcan, Roberta La Piana, Luke M. Healy","doi":"10.1186/s13024-024-00723-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00723-x","url":null,"abstract":"Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL. The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1RWT/KO and CSF1RWT/E633K iMGL compared to their respective isogenic controls. We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"28 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140534568","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}