Visualizing alpha-synuclein and iron deposition in M83 mouse model of Parkinson's disease in vivo.

Publisher: International Society of Neuropathology Country of Publication: Switzerland NLM ID: 9216781 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1750-3639 (Electronic) Linking ISSN: 10156305 NLM ISO Abbreviation: Brain Pathol Subsets: MEDLINE

Original Publication: Zürich, Switzerland : International Society of Neuropathology, [1990-

alpha-Synuclein*/metabolism ; Brain*/metabolism ; Brain*/pathology ; Brain*/diagnostic imaging ; Disease Models, Animal* ; Iron*/metabolism ; Parkinson Disease*/metabolism ; Parkinson Disease*/pathology; Animals ; Female ; Humans ; Male ; Mice ; Inclusion Bodies/metabolism ; Inclusion Bodies/pathology ; Magnetic Resonance Imaging/methods ; Mice, Transgenic

Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe ³⁺ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.
(© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Update of: bioRxiv. 2023 Jun 30:2023.06.28.546962. doi: 10.1101/2023.06.28.546962. (PMID: 37425954)

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R01-NS126102-01 United States NH NIH HHS; 31ND30_213444 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung; Fondation Gustave et Simone Prévot; AP22-02 Swiss Center for Applied Human Toxicology; 310030_192757 Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung; Parkinson Schweiz; Novartis Stiftung für Medizinisch-Biologische Forschung; Olga Mayenfisch Stiftung; RF1 NS126102 United States NS NINDS NIH HHS; 51767.1 IP-LS Innosuisse - Schweizerische Agentur für Innovationsförderung; 2018PI-03 Dementia Research Switzerland-Foundation Synapsis

Keywords: Parkinson's disease; alpha‐synuclein; fluorescence imaging; iron; magnetic resonance imaging; optoacoustic imaging; susceptibility weighted imaging

0 (alpha-Synuclein)
E1UOL152H7 (Iron)

Date Created: 20240710 Date Completed: 20241016 Latest Revision: 20241025

20241025

PMC11483525

10.1111/bpa.13288

38982662