Isotope-encoded spatial biology identifies plaque-age-dependent maturation and synaptic loss in an Alzheimer’s disease mouse model
Year: 2025
Type: article
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.
Source: Nature Communications
Authors: 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, Jörg Hanrieder
Institutions: University College London, University of Gothenburg, Sahlgrenska University Hospital, UCL Queen Square Institute of Neurology, University of Science and Technology of China, Sorbonne Université, Institut des Sciences Moléculaires, Pitié-Salpêtrière Hospital, Institut du Cerveau, University of Wisconsin–Madison, UK Dementia Research Institute, Northwestern University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Gun och Bertil Stohnes Stiftelse, EU Joint Programme – Neurodegenerative Disease Research, University College London, European Commission, Vetenskapsrådet, Magnus Bergvalls Stiftelse, Fondation pour la Recherche sur Alzheimer, National Institutes of Health, HORIZON EUROPE Framework Programme, National Institute on Aging
Awards: G1057200632, G1088883541, G1135383168, G1222782219, G1253720191, The Alzheimer’s Association quality control (QC) program for CSF and plasma biomarkers - Continuation, G1551449788, G1586157608, G1588116593, G1771944843, G1802301745, Understanding Alzheimer Blood Biomarkers for Tau Pathology, G201353144, G2108271864, G2501682398, The Alzheimer biomarker toolbox – use in pathogenic studies, diagnostics and theragnostics, G2841269746, G2879339865, G292763017, G2956353840, G313301595, G3241251457, Fluid biomarkers for neurodegenerative dementias, G3903502641, G3914690605, G4181470480, G4234328627, G4260843567, G432431387, G434337789, G4404751248, G5040492720, G506008078, Tau pathology in Alzheimer´s - understanding pathophysiology through biomarkers in blood and CSF, Fluid biomarkers for neurodegenerative dementias, G5749088205, CASCADE: CAuSe or Consequence in Alzheimer DiseasE?, Insights into Amyloid Pathogenicity Dynamics, G6158734006, G6168044258, G6289970089, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G6745400708, G691317373, G7143958211, Orbitrap Eclipse Mass Spectrometer for Northwestern University Neuroproteomic Collaboration Hub, G7748812462, G791739130, AMYCHRON – Amyloid Chronology to Understand Aβ Pathogenicity in Alzheimers disease, G8471698345, Human in vivo stable isotope labeling kinetics (iSILK) to quantify brain amyloid plaque kinetics, G9000041326, G9000305866, Understanding Amyloid Pathology - Multiomic Activity Imaging of Plaque Formation Dynamics (AmyMAP)
OpenAlex ID: W4413884099