Brain, CSF, and Blood Metabolomics Signature in the TgF344-AD Rat Model of Alzheimer’s Disease

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, affecting millions of elderly patients and representing a common cause of dementia worldwide. Among the molecular and cellular processes involved in AD pathogenesis, the extracellular aggregation of β-amyloid (Aβ) has been strongly linked to AD progression. As AD advances, the metabolic profiles of the brain and other organs undergo significant changes. Metabolomics serves as an invaluable tool for discovering biomarkers to enable early diagnosis of AD. Using liquid chromatography-mass spectrometry (LC-MS), we analyzed brain tissues (from the frontal cortex and hippocampus), cerebrospinal fluid, and plasma from TgF344-AD rats (n = 8 males) and wild-type rats (n = 8), aged 7 months, identifying 710 analytically robust metabolites across the four biological matrices. A similar methodology was applied to 12 rats aged 22 months. Our results highlighted that the metabolomic profiles and altered metabolic pathways varied between early and advanced stages in both central and peripheral matrices. At 7 months, the metabolic fingerprint showed alterations predominantly affecting amino acid and lipid metabolism, whereas by 22 months, it shifted to a distinct fingerprint impacting amino acid, lipid, and nucleotide metabolism. These findings provide insights that could support the development of diagnostic tools and targeted therapeutic strategies tailored to each stage of the disease.