Quantitative 3D histochemistry reveals region-specific amyloid-β reduction by the antidiabetic drug netoglitazone
A hallmark of Alzheimer's disease (AD) is the extracellular aggregation of toxic amyloid-beta (Aβ) peptides in form of plaques. Here, we identify netoglitazone, an antidiabetic compound previously tested in humans, as an Aβ aggregation antagonist. Netoglitazone improved cognition and reduced microglia activity in a mouse model of AD. Using quantitative whole-brain three-dimensional histology (Q3D), we precisely identified brain regions where netoglitazone reduced the number and size of Aβ plaques. We demonstrate the utility of Q3D in preclinical drug evaluation for AD by providing a high-resolution brain-wide view of drug efficacy. Applying Q3D has the potential to improve pre-clinical drug evaluation by providing information that can help identify mechanisms leading to brain region-specific drug efficacy.
Authors
- Francesca Catto (ORCID: https://orcid.org/0000-0002-0429-2552)
- Adriano Aguzzi (ORCID: https://orcid.org/0000-0002-0344-6708)
- Athena Economides (ORCID: https://orcid.org/0000-0003-2340-6364)
- Ulrike Weber‐Stadlbauer (ORCID: https://orcid.org/0000-0002-5278-9993)
- Ehsan Dadgar‐Kiani (ORCID: https://orcid.org/0000-0002-4111-9820)
- Lukas Frick (ORCID: https://orcid.org/0000-0002-2147-5369)
- Daniel S. Kirschenbaum (ORCID: https://orcid.org/0000-0002-0609-8788)
- Anna Maria Reuss (ORCID: https://orcid.org/0000-0003-1096-3030)
- Chiara Trevisan (ORCID: https://orcid.org/0000-0002-3997-094X)
- Petros Koumoutsakos (ORCID: https://orcid.org/0000-0001-8337-2122)
- Sergey Litvinov (ORCID: https://orcid.org/0000-0001-9152-4835)
- Davide Caredio (ORCID: https://orcid.org/0000-0002-3723-894X)
- Jin Hyung Lee (ORCID: https://orcid.org/0000-0001-7540-1018)
- Delic Mirzet
Institutions
- Harvard University (US)
- University of Zurich (CH)
- ETH Zurich (CH)
- University Hospital of Zurich (CH)
- Infrastructure Management Consultants (Switzerland) (CH)
- Neurological Surgery (US)
- Stanford University (US)
Publication Details
- Journal
- PLoS ONE
- Published
- 2025-05-06
- DOI
- https://doi.org/10.1371/journal.pone.0309489
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Michael J. Fox Foundation for Parkinson's Research
- Human Frontier Science Program
- Fondazione Gelu
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- NOMIS Stiftung