Divergent toxicity mechanisms of amyloid-beta aggregates arising from a single aggregation reaction.

Stage-specific Aβ42 aggregates from a single aggregation reaction show divergent toxicity in murine organotypic brain slices, with lag-phase species elevating Ca2+ and impairing LTP.

• Why it matters: Amyloid-β aggregation is an early AD sign, but how different aggregation stages translate into distinct cellular toxicity mechanisms is unclear.
• What they did: The study characterized Aβ42 species at multiple aggregation stages at the single-molecule level and tested their toxicity in murine organotypic brain slices.
• The result: Lag-phase aggregates elevated neuronal baseline Ca2+ and impaired LTP while promoting microglial homeostatic exit and DAM transition; growth-phase aggregates downregulated homeostatic microglial markers and triggered TLR4-mediated activation, cytokines, complement activation, synaptic engulfment, and severe neuronal disruption.

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