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

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

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

2025
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Overview
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 1-40 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. Understanding synapse loss in Alzheimer’s disease has been hampered by a lack of human model systems. Here, the authors show that manipulation of physiological or pathological Aβ has differing effects on synapses in live human brain slice cultures.