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A large-scale volumetric correlated light and electron microscopy study localizes Alzheimer’s disease-related molecules in the hippocampus
| العنوان: | A large-scale volumetric correlated light and electron microscopy study localizes Alzheimer’s disease-related molecules in the hippocampus |
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| المؤلفون: | Han, Xiaomeng, Li, Peter, H, Wang, Shuohong, Sanchez, Morgan, Aggarwal, Sneha, Blakely, Tim, Schalek, Richard, Meirovitch, Yaron, Lin, Zudi, Berger, Daniel, Wu, Yuelong, Aly, Fatima, Bay, Sylvie, Delatour, Benoît, Lafaye, Pierre, Pfister, Hanspeter, Wei, Donglai, Jain, Viren, Ploegh, Hidde, Lichtman, Jeff |
| المساهمون: | Harvard University, Google Research, Harvard Medical School Boston (HMS), Boston College (BC), Harvard College Cambridge, MA, USA, Chimie des Biomolécules - Chemistry of Biomolecules, Institut Pasteur Paris (IP)-Institut de Chimie - CNRS Chimie (INC-CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière AP-HP, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des Anticorps (plate-forme) - Antibody Engineering (Platform), Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Boston Children's Hospital, This work was supported by NIH grants U19 NS104653, UG3 MH123386, and P50 MH094271 (J. W. L.), NSF grants NSF-CAREER-2239688 (D. W.), NCS-FO-2124179, and NCS-FO-1835231 (H. Pfister.), NLM T15LM007092-31 (M. S.), Office of Naval Research grant N00014-20-1-2828 (J. W. L). X. H. was supported by the Edward R. and Anne G. Lefler predoctoral fellowship from the Lefler Center for Neurodegenerative Disorders at Harvard Medical School and the Simmons Awards from the Harvard Center for Biological Imaging. |
| المصدر: | https://hal.science/hal-04793566 ; 2024. |
| بيانات النشر: | HAL CCSD |
| سنة النشر: | 2024 |
| مصطلحات موضوعية: | Aβ40/42 hyperphosphorylated tau CD11b microglia nanobody hippocampus CA1 ultrastructure synapse volume electron microscopy serial section electron microscopy connectomics, Aβ40/42, hyperphosphorylated tau, CD11b, microglia, nanobody, hippocampus CA1, ultrastructure, synapse, volume electron microscopy, serial section electron microscopy, connectomics, [SDV]Life Sciences [q-bio] |
| الوصف: | Connectomics is a nascent neuroscience field to map and analyze neuronal networks. It provides a new way to investigate abnormalities in brain tissue, including in models of Alzheimer's disease (AD). This age-related disease is associated with alterations in amyloid-β (Aβ) and phosphorylated tau (pTau). These alterations correlate with AD's clinical manifestations, but causal links remain unclear. Therefore, studying these molecular alterations within the context of the local neuronal and glial milieu may provide insight into disease mechanisms. Volume electron microscopy (vEM) is an ideal tool for performing connectomics studies at the ultrastructural level, but localizing specific biomolecules within large-volume vEM data has been challenging. Here we report a volumetric correlated light and electron microscopy (vCLEM) approach using fluorescent nanobodies as immuno-probes to localize Alzheimer's diseaserelated molecules in a large vEM volume. Three molecules (pTau, Aβ, and a marker for activated microglia (CD11b)) were labeled without the need for detergents by three nanobody probes in a sample of the hippocampus of the 3xTg Alzheimer's disease model mouse. Confocal microscopy followed by vEM imaging of the same sample allowed for registration of the location of the molecules within the volume. This dataset revealed several ultrastructural abnormalities regarding the localizations of Aβ and pTau in novel locations. For example, two pTau-positive post-synaptic spine-like protrusions innervated by axon terminals were found projecting from the axon initial segment of a pyramidal cell. Three pyramidal neurons with intracellular Aβ or pTau were 3D reconstructed. Automatic synapse detection, which is necessary for connectomics analysis, revealed the changes in density and volume of synapse at different distances from an Aβ plaque. This vCLEM approach is useful to uncover molecular alterations within large-scale volume electron microscopy data, opening a new connectomics pathway to study Alzheimer's disease and ... |
| نوع الوثيقة: | report |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/37961104; BIORXIV: 2023.10.24.563674; PUBMED: 37961104; PUBMEDCENTRAL: PMC10634883 |
| DOI: | 10.1101/2023.10.24.563674 |
| الاتاحة: | https://hal.science/hal-04793566 https://hal.science/hal-04793566v1/document https://hal.science/hal-04793566v1/file/2023.10.24.563674v1.full.pdf https://doi.org/10.1101/2023.10.24.563674 |
| Rights: | http://hal.archives-ouvertes.fr/licences/copyright/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.517D67E5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1101/2023.10.24.563674 |
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