Opposing roles 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 Martin Brennan; Claire S. Durrant

doi:10.1038/s41467-025-58879-z

NeuroscienceNature CommunicationsApr 30, 2025

Peer-reviewed journal article

Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures

Robert I. McGeachan iD, Soraya Meftah iD, Lewis W. Taylor iD, James H. Catterson iD, Danilo Negro iD, Calum Bonthron iD, Kristján Holt iD, Jane Tulloch iD, Jamie L. Rose iD, Francesco Gobbo iD, Ya Yin Chang iD, Jamie Elliott iD, Lauren McLay iD, Declan King iD, Imran Liaquat, Tara L. Spires‐Jones iD, Sam A. Booker iD, Paul Martin Brennan iD, Claire S. Durrant iD

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Abstract

In Alzheimers disease, it is theorised that amyloid beta (A{beta}) and tau pathology contribute to synapse loss. However, there is limited information on how endogenous levels of tau and A{beta} protein relate to patient characteristics, or how manipulating physiological levels of A{beta} impacts synapses, in living adult, human brain. Here, we employed live human brain slice cultures as a translational tool to assess endogenous tau and A{beta} release, pathology, and response to experimental manipulation. We found that the levels of A{beta}1-40 and tau detected in the culture medium depend on donor age, and brain region, respectively. Pharmacologically raising physiological A{beta} concentration enhanced levels of synaptic transcripts. Treatment of slices with A{beta}-containing Alzheimers disease brain extract resulted in postsynaptic A{beta} uptake and loss of presynaptic puncta. These data indicate that physiological and pathological A{beta} can have opposing effects on synapses in living human brain tissue.