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

Simone Zuffa; Celeste Allaband; Vincent Charron‐Lamoureux; Andrés Mauricio Caraballo‐Rodríguez; Abubaker Patan; Ipsita Mohanty; Julius Agongo; John W. Bostick; T. Jaymie Connerly; Taren Thron; Brittany Needam; Matheus de Castro Fonseca; Rodolfo A. Salido; Lauren Hansen; Helena M. Tubb; Jennifer H. Cao; Karel Kalecký; Teodoro Bottiglieri; Siamak MahmoudianDehkordi; Leyla Schimmel; Alexandra Kueider‐Paisley; Stewart Francis Graham; Dionicio R. Siegel; Mingxun Wang; Rob D. Knight; Rima F Kaddurah-Daouk; Pieter C. Dorrestein; Sarkis K. Mazmanian

doi:10.1101/2025.04.28.651123

MicrobiologybioRxivApr 28, 2025

Preprint

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

Simone Zuffa iD, Celeste Allaband iD, Vincent Charron‐Lamoureux iD, Andrés Mauricio Caraballo‐Rodríguez iD, Abubaker Patan iD, Ipsita Mohanty iD, Julius Agongo iD, John W. Bostick iD, T. Jaymie Connerly iD, Taren Thron iD, Brittany Needam, Matheus de Castro Fonseca iD, Rodolfo A. Salido iD, Lauren Hansen, Helena M. Tubb iD, Jennifer H. Cao iD, Karel Kalecký iD, Teodoro Bottiglieri iD, Siamak MahmoudianDehkordi iD, Leyla Schimmel iD, Alexandra Kueider‐Paisley iD, Stewart Francis Graham iD, Dionicio R. Siegel iD, Mingxun Wang iD, Rob D. Knight iD, , Sarkis K. Mazmanian iD

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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