The interwoven fibril-like structure of amyloid-beta plaques in mouse brain tissue visualized using super-resolution STED microscopy
Johansson, Björn (Karolinska University Hospital)
Oasa, Sho (Karolinska Institutet. Department of Clinical Neuroscience (Estocolm, Suècia))
Muntsant, Aida (Universitat Autònoma de Barcelona. Departament de Psiquiatria i de Medicina Legal)
Tiiman, Ann (Karolinska Institutet. Department of Clinical Neuroscience (Estocolm, Suècia))
Söderberg, Linda (BioArctic (Stockholm, Suècia))
Amandius, Ebba (BioArctic (Stockholm, Suècia))
Möller, Christer (BioArctic (Stockholm, Suècia))
Lannfelt, Lars (BioArctic (Stockholm, Suècia))
Terenius, Lars (Karolinska Institutet. Department of Clinical Neuroscience (Estocolm, Suècia))
Gimenez-Llort, Lydia (Universitat Autònoma de Barcelona. Departament de Psiquiatria i de Medicina Legal)
Vukojević, Vladana (Karolinska Institutet. Department of Clinical Neuroscience (Estocolm, Suècia))

Data:	2023
Resum:	Standard neuropathologic analysis of Alzheimer's brain relies on traditional fluorescence microscopy, which suffers from limited spatial resolution due to light diffraction. As a result, it fails to reveal intricate details of amyloid plaques. While electron microscopy (EM) offers higher resolution, its extensive sample preparation, involving fixation, dehydration, embedding, and sectioning, can introduce artifacts and distortions in the complex brain tissue. Moreover, EM lacks molecular specificity and has limited field of view and imaging depth. In our study, we employed super-resolution Stimulated Emission Depletion (STED) microscopy in conjunction with the anti-human APP recombinant antibody 1C3 fluorescently labelled with DyLight TM 633 (1C3-DyLight633). This combination allowed us to visualize amyloidogenic aggregates in vitro and in brain sections from a 17-month-old 3×Tg-AD mouse with sub-diffraction limited spatial resolution. Remarkably, we achieved a spatial resolution of 29 nm in vitro and 62 nm in brain tissue sections, surpassing the capabilities of conventional confocal microscopy by 5-10 times. Consequently, we could discern individual fibrils within plaques, an achievement previously only possible with EM. The utilization of STED microscopy represents a groundbreaking advancement in the field, enabling researchers to delve into the characterization of local mechanisms that underlie Amyloid (Aβ) deposition into plaques and their subsequent clearance. This unprecedented level of detail is especially crucial for comprehending the etiology of Alzheimer's disease and developing the next generation of anti-amyloid treatments. By facilitating the evaluation of drug candidates and non-pharmacological interventions aiming to reduce amyloid burden, STED microscopy emerges as an indispensable tool for driving scientific progress in Alzheimer's research.
Ajuts:	European Commission 26408 European Commission 737390
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Alzheimer's disease ; Amyloid beta peptide ; Amyloid fibrils ; Immunohistochemistry ; Super-resolution STED microscopy ; Next generation drug design
Publicat a:	Cell & Bioscience, Vol. 13 (august 2023) , ISSN 2045-3701

DOI: 10.1186/s13578-023-01086-4
PMID: 37542303

9 p, 1.3 MB

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