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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.
Authors
Xiaohang Qian, Zhongxuan Wang, Siyue Chen, Yang Xue, Yawen Yang, Peijing Cui, Miao Zhang, Huidong Tang
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