Related Experiment Videos
Purine metabolism disruption links pathology and cognitive decline in Alzheimer's disease
Xiaohang Qian1,2, Zhongxuan Wang1, Siyue Chen1
1Department of Geriatrics, Medical Center on Aging, Ruijin Hospital.
Abstract:
Purine metabolism dysregulation has been implicated in Alzheimer's disease (AD), but its temporal dynamics and mechanistic links to core pathologies remain unclear. This translational study integrated a longitudinal preclinical AD mouse model and clinical cohort investigations to define the role of purine metabolism in AD progression. In APPswe/PSEN1dE9 (APP/PS1) mice, serum-untargeted metabolomics identified purine metabolism as the most notably altered pathway, with metabolite levels (e.g., adenine, adenosine) shifting dynamically across disease stages alongside increasing amyloid-β (Aβ) burden. In the pathology-defined clinical cohort, targeted analysis revealed that serum uric acid and allantoin were specifically depleted in the Aβ+ cognitively impaired (CI) group and correlated strongly with higher brain Aβ load, increased neuroinflammation, and poorer cognitive scores. Formal mediation analysis elucidated a plausible mechanistic cascade: the association of uric acid/allantoin with cognitive impairment was primarily mediated by Aβ pathology. Two-year longitudinal data further suggest that changes in specific purine metabolites might predict the rate of cognitive decline. Allantoin supplementation reduced Aβ pathology through promoting microglial phagocytosis of Aβ in APP/PS1 mice. Our findings identified purine metabolism as a key hub connecting Aβ pathology, neuroinflammation, and clinical progression in AD.
Related Concept Videos
Alzheimer Disease ll: Pathophysiology
Alzheimer Disease l: Introduction
Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ and tau...
Biosynthesis of Nucleic Acids
Dementia l: Introduction
Parkinson Disease ll: Pathophysiology