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

McGeachan, R. I.; Meftah, S.; Taylor, L. W.; Catterson, J. H.; Negro, D.; Tulloch, J.; Rose, J. L.; Gobbo, F.; Liaquat, I.; Spires-Jones, T. L.; Booker, S. A.; Brennan, P. M.; Durrant, C. S.

doi:10.1101/2024.02.16.580676

bioRxiv · 10.1101/2024.02.16.580676

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

McGeachan, R. I.·Meftah, S.·Taylor, L. W.·Catterson, J. H.·Negro, D.·Tulloch, J.·Rose, J. L.·Gobbo, F.·Liaquat, I.·Spires-Jones, T. L.·Booker, S. A.·Brennan, P. M.·Durrant, C. S.

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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.

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McGeachan, R. I., Meftah, S., Taylor, L. W., Catterson, J. H., Negro, D., Tulloch, J., Rose, J. L., Gobbo, F., Liaquat, I., Spires-Jones, T. L., Booker, S. A., Brennan, P. M., Durrant, C. S.. 2024-02-21. Opposing roles of physiological and pathological amyloid-β on synapses in live human brain slice cultures. https://doi.org/10.1101/2024.02.16.580676

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