Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic

Alberto Siddu; Silvia Natale; Connie H. Wong; Hamidreza Shaye; Thomas C. Südhof

doi:10.1172/JCI193407

Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic

Alberto Siddu,¹ Silvia Natale,² Connie H. Wong,² Hamidreza Shaye,² and Thomas C. Südhof¹

Published September 30, 2025 - More info

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Abstract

Whether amyloid-β (Aβ) peptides are synaptogenic or synaptotoxic remains a pivotal open question in Alzheimer’s disease research. Here, we chronically treated human neurons with precisely controlled concentrations of chemically defined synthetic Aβ40, Aβ42, and Aβ42^arctic peptides that exhibit distinct aggregation propensities. Remarkably, chronic exposure of human neurons to free Aβ40 at higher concentrations or to free Aβ42 at lower concentrations potently promoted synapse formation. In contrast, aggregated Aβ42 or Aβ42^arctic at higher concentrations were neurotoxic and synaptotoxic. The synaptotoxic effects of Aβ peptides manifested as an initial contraction of the synaptic vesicle cluster followed by synapse loss. Aβ40 and Aβ42 peptides with scrambled or inverted sequences were inactive. Thus, our experiments reveal that Aβ peptides exhibit an aggregation-dependent functional dichotomy that renders them either synaptogenic or synaptotoxic, thereby providing insight into how Aβ peptides straddle a thin line between physiological synapse organization and pathological synapse disruption. Among others, our data suggest that Alzheimer’s disease therapies might aim to shift the balance of Aβ peptides from the aggregated to the free state instead of suppressing all Aβ peptides.

Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic

Alberto Siddu,¹ Silvia Natale,² Connie H. Wong,² Hamidreza Shaye,² and Thomas C. Südhof¹

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Aggregation shifts amyloid-β peptides from synaptogenic to synaptotoxic

Alberto Siddu,1 Silvia Natale,2 Connie H. Wong,2 Hamidreza Shaye,2 and Thomas C. Südhof1

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Alberto Siddu,¹ Silvia Natale,² Connie H. Wong,² Hamidreza Shaye,² and Thomas C. Südhof¹