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

  • Cell Rep. 2026 Jun 22;45(7):117595. doi: 10.1016/j.celrep.2026.117595.
Vanya Metodieva  1 ,  Sybille Marchese  1 ,  Pietro Esposito  1 ,  John S H Danial  2 ,  Andrea Di Falco  2 ,  Suman De  3 ,  David Klenerman  4 ,  Juan A Varela  5
Affiliations
  • 1. School of Biology, University of St Andrews, St Andrews, UK.
  • 2. School of Physics and Astronomy, University of St Andrews, St Andrews, UK.
  • 3. Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
  • 4. Department of Chemistry, University of Cambridge, Cambridge, UK; UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
  • 5. School of Physics and Astronomy, University of St Andrews, St Andrews, UK. Electronic address: [email protected].
PMID: 42329766 DOI: 10.1016/j.celrep.2026.117595
Abstract

Amyloid-β 1-42 (Aβ42) aggregation is among the earliest pathological signs in Alzheimer's disease (AD). Here, we characterized Aβ42 species at several aggregation stages at the single-molecule level and examined their toxicity in murine organotypic brain slices, where we observed a stage-dependent recapitulation of multiple aspects of the cellular phase of AD. Aggregates formed during the lag phase of the Aβ42 aggregation elevated neuronal baseline CA2+ levels and impaired long-term potentiation (LTP), while promoting microglial homeostatic exit and transition to disease-associated microglia (DAM) state. In contrast, aggregates enriched during the growth phase downregulated homeostatic microglial markers and induced TLR4-mediated microglial activation, cytokine production, and complement activation, leading to synaptic engulfment and severe disruption of neuronal activity. Together, these findings reveal that structurally distinct Aβ42 aggregate species engage different cellular and molecular pathways. This framework advances mechanistic understanding of amyloid toxicity in neurodegeneration and could inform the design of combination therapeutic strategies.

Keywords
Alzheimer’s disease; CP: molecular biology; CP: neuroscience; DAM; TAK-242; TLR4; amyloid-beta; calcium imaging; inflammation; microglia; organotypic hippocampal slices; single-molecule imaging.
Products