Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures
In Alzheimer's disease, amyloid beta (Aβ) and tau pathology are thought to drive synapse loss. However, there is limited information on how endogenous levels of tau, Aβ and other biomarkers relate to patient characteristics, or how manipulating physiological levels of Aβ impacts synapses in living adult human brain. Using live human brain slice cultures, we report that Aβ<sub>1-40</sub> and tau release levels vary with donor age and brain region, respectively. Release of other biomarkers such as KLK-6, NCAM-1, and Neurogranin vary between brain region, while TDP-43 and NCAM-1 release is impacted by sex. Pharmacological manipulation of Aβ in either direction results in a loss of synaptophysin puncta, with increased physiological Aβ triggering potentially compensatory synaptic transcript changes. In contrast, treatment with Aβ-containing Alzheimer's disease brain extract results in post-synaptic Aβ uptake and pre-synaptic puncta loss without affecting synaptic transcripts. These data reveal distinct effects of physiological and pathological Aβ on synapses in human brain tissue.
Authors
- Claire S. Durrant (ORCID: https://orcid.org/0000-0001-7552-7358)
- Francesco Gobbo (ORCID: https://orcid.org/0000-0002-8331-929X)
- Jamie Rose (ORCID: https://orcid.org/0000-0002-8110-376X)
- Imran Liaquat
- Jane Tulloch (ORCID: https://orcid.org/0009-0005-6975-5430)
- Ya Yin Chang (ORCID: https://orcid.org/0000-0001-9794-403X)
- Kristján Holt (ORCID: https://orcid.org/0000-0003-3903-6361)
- Sam A. Booker (ORCID: https://orcid.org/0000-0003-1980-9873)
- James H. Catterson (ORCID: https://orcid.org/0000-0003-4231-0114)
- Robert I. McGeachan (ORCID: https://orcid.org/0000-0003-1647-8642)
- Calum Bonthron
- Declan King (ORCID: https://orcid.org/0000-0002-2434-9317)
- S. Meftah (ORCID: https://orcid.org/0000-0002-3408-5626)
- Paul Martin Brennan (ORCID: https://orcid.org/0000-0002-7347-830X)
- Janet Elliott (ORCID: https://orcid.org/0009-0003-7684-7646)
- Tara L. Spires‐Jones (ORCID: https://orcid.org/0000-0003-2530-0598)
- Danilo Negro (ORCID: https://orcid.org/0000-0001-5858-1133)
- Lewis W. Taylor (ORCID: https://orcid.org/0009-0002-2531-6696)
- Lauren McLay
Institutions
- Edinburgh Cancer Research (GB)
- Edinburgh Royal Infirmary (GB)
- UK Dementia Research Institute (GB)
- University of Edinburgh (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-30
- DOI
- https://doi.org/10.1038/s41467-025-58879-z
- Citations
- 12
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 13.97
Funders
- Wellcome
- Wellcome Trust
- Dyson Foundation
- James Dyson Foundation
- Alzheimer's Society
- UK Dementia Research Institute
- Medical Research Council