Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer’s disease mouse model

Jack I. Wood, Maciej Dulewicz, Alicja Szadziewska, Sophia Weiner, Junyue Ge, Katie Stringer, Sneha Desai, Lydia Fenson, Diana Piotrowska, Gunnar Brinkmalm, Srinivas Koutarapu, Haady B. Hajar, Kaj Blennow, Henrik Zetterberg, Damian M. Cummings, Jeffrey N. Savas, Frances A. Edwards and Jörg Hanrieder ()
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Jack I. Wood: University of Gothenburg
Maciej Dulewicz: University of Gothenburg
Alicja Szadziewska: University of Gothenburg
Sophia Weiner: University of Gothenburg
Junyue Ge: University of Gothenburg
Katie Stringer: University of Gothenburg
Sneha Desai: University of Gothenburg
Lydia Fenson: University of Gothenburg
Diana Piotrowska: University of Gothenburg
Gunnar Brinkmalm: University of Gothenburg
Srinivas Koutarapu: University of Gothenburg
Haady B. Hajar: University College London
Kaj Blennow: University of Gothenburg
Henrik Zetterberg: University of Gothenburg
Damian M. Cummings: University College London
Jeffrey N. Savas: Northwestern University
Frances A. Edwards: University College London
Jörg Hanrieder: University of Gothenburg

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Understanding how amyloid beta (Aβ) plaques develop and lead to neurotoxicity in Alzheimer’s disease remains a major challenge, particularly given the temporal delay and weak correlation between plaque deposition and cognitive decline. This study investigates how the evolving pathology of plaques affects the surrounding tissue, using a knock-in Aβ mouse model (AppNL-F/NL-F). We combined mass spectrometry imaging with stable isotope labeling to timestamp Aβ plaques from the moment of their initial deposition, enabling us to track their aging spatially. By integrating spatial transcriptomics, we linked changes in gene expression to the age of the plaques, independent of the mice’s chronological age or disease stage. Here we show that older plaques were associated with reduced expression of synaptic genes. Additionally, when correlated with structure-specific dyes, we show that plaque age positively correlated with structural maturation. These more compact and older plaques were linked to greater synapse loss and increased toxicity.

Date: 2025
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DOI: 10.1038/s41467-025-63328-y

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