Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer's disease mouse model PMID: 40890115

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2025 Sep 1;16(1):8170. doi: 10.1038/s41467-025-63328-y.

Jack I Wood ^# ¹ ² , Maciej Dulewicz ^# ¹ ³ , Alicja Szadziewska ¹ , Sophia Weiner ¹ ⁴ ⁵ , Junyue Ge ¹ , Katie Stringer ¹ ² , Sneha Desai ¹ ² , Lydia Fenson ¹ , Diana Piotrowska ¹ , Gunnar Brinkmalm ¹ ⁶ , Srinivas Koutarapu ¹ , Haady B Hajar ² , Kaj Blennow ¹ ⁶ ⁷ ⁸ , Henrik Zetterberg ¹ ⁴ ⁶ ⁹ ¹⁰ ¹¹ , Damian M Cummings ² , Jeffrey N Savas ¹² , Frances A Edwards ² , Jörg Hanrieder ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
2. Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom.
3. Department of Neuropsychiatry, Sahlgrenska University Hospital, Mölndal, Sweden.
4. Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queens Square, London, United Kingdom.
5. Dementia Research Centre, Queen Square Institute of Neurology, University College London, Queens Square, London, United Kingdom.
6. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal Hospital, House V, Mölndal, Sweden.
7. Paris Brain Institute, ICM, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France.
8. Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, P. R. China.
9. UK Dementia Research Institute at UCL, London, UK.
10. Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, PR China.
11. Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
12. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
13. Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden. [email protected].
14. Department of Neuropsychiatry, Sahlgrenska University Hospital, Mölndal, Sweden. [email protected].
15. Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, Queens Square, London, United Kingdom. [email protected].
16. Dementia Research Centre, Queen Square Institute of Neurology, University College London, Queens Square, London, United Kingdom. [email protected].
# Contributed equally.

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 (App^NL-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.