A Multi-Organ Murine Metabolomics Atlas Reveals Molecular Dysregulations in Alzheimer's Disease

Zuffa, S.; Allaband, C.; Charron-Lamoureux, V.; Caraballo-Rodriguez, A. M.; Patan, A.; Mohanty, I.; Agongo, J.; Bostick, J. W.; Connerly, T.; Thron, T.; Needham, B.; de Castro Fonseca, M.; Salido, R.; Hansen, L.; Tubb, H.; Cao, J.; Kalecky, K.; Bottiglieri, T.; MahmoudianDehkordi, S.; Schimmel, L.; Kueider-Paisley, A.; Graham, S.; Siegel, D.; Wang, M.; Knight, R.; Kaddurah-Daouk, R.; Dorrestein, P. C.; Mazmanian, S.

doi:10.1101/2025.04.28.651123

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bioRxiv · 10.1101/2025.04.28.651123

A Multi-Organ Murine Metabolomics Atlas Reveals Molecular Dysregulations in Alzheimer's Disease

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Abstract

The etiology of Alzheimers Disease (AD) remains largely unclear but is likely driven by gene-environment interactions. Here, we present a multi-organ untargeted metabolomics dataset (2,271 samples) generated from five tissue types in two genetic AD mouse models under colonized or germ-free conditions, complemented by shotgun metagenomics sequencing data (666 samples). Systems-level analyses of 3xTg and 5xFAD mice reveal clusters of dysregulated molecular classes across tissues including carnitines, bile acids, B vitamins, and neurotransmitters. This signature, coupled with microbiome profiles, suggests increased oxidative stress via mitochondrial dysfunction. Molecular feature tracking via tissueMASST, a mass spectrometry search tool we developed to bridge animal model findings with human data, identifies microbially-modulated phenylacetyl-carnitine as positively associated with aging and cognitive impairment across human AD studies. With hundreds of yet-to-be-characterized metabolites, this public resource and its associated tools will aid future research in the pathophysiology of AD.

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Zuffa, S., Allaband, C., Charron-Lamoureux, V., Caraballo-Rodriguez, A. M., Patan, A., Mohanty, I., Agongo, J., Bostick, J. W., Connerly, T., Thron, T., Needham, B., de Castro Fonseca, M., Salido, R., Hansen, L., Tubb, H., Cao, J., Kalecky, K., Bottiglieri, T., MahmoudianDehkordi, S., Schimmel, L., Kueider-Paisley, A., Graham, S., Siegel, D., Wang, M., Knight, R., Kaddurah-Daouk, R., Dorrestein, P. C., Mazmanian, S.. 2025-04-28. A Multi-Organ Murine Metabolomics Atlas Reveals Molecular Dysregulations in Alzheimer's Disease. https://doi.org/10.1101/2025.04.28.651123

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