Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures

Robert I. McGeachan, Soraya Meftah, Lewis W. Taylor, James H. Catterson, Danilo Negro, Calum Bonthron, Kristján Holt, Jane Tulloch, Jamie L. Rose, Francesco Gobbo, Ya Yin Chang, Jamie Elliott, Lauren McLay, Declan King, Imran Liaquat, Tara L. Spires-Jones, Sam A. Booker, Paul M. Brennan and Claire S. Durrant ()
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Robert I. McGeachan: The University of Edinburgh
Soraya Meftah: The University of Edinburgh
Lewis W. Taylor: The University of Edinburgh
James H. Catterson: The University of Edinburgh
Danilo Negro: The University of Edinburgh
Calum Bonthron: The University of Edinburgh
Kristján Holt: The University of Edinburgh
Jane Tulloch: The University of Edinburgh
Jamie L. Rose: The University of Edinburgh
Francesco Gobbo: The University of Edinburgh
Ya Yin Chang: The University of Edinburgh
Jamie Elliott: The University of Edinburgh
Lauren McLay: The University of Edinburgh
Declan King: The University of Edinburgh
Imran Liaquat: Royal Infirmary of Edinburgh
Tara L. Spires-Jones: The University of Edinburgh
Sam A. Booker: The University of Edinburgh
Paul M. Brennan: Royal Infirmary of Edinburgh
Claire S. Durrant: The University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract 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 Aβ1-40 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.

Date: 2025
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DOI: 10.1038/s41467-025-58879-z

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