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

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