Structural Superimposition

Abstact

Dysregulated tricarboxylic acid (TCA) cycle activity is increasingly recognized as a contributor to Alzheimer's disease (AD) pathogenesis, yet the mechanistic underpinnings of the relationship remain unclear. Here, we identify isocitrate dehydrogenase 1 (IDH1), a key enzyme in the TCA cycle, as a critical pathogenic driver of AD in microglia. IDH1 expression was markedly upregulated in microglia from both AD patients and 5xFAD mice. Elevated IDH1 promoted excessive cytosolic citrate consumption, which restricted citrate shuttling into mitochondria and impaired mitochondrial TCA cycle function. This citrate metabolic imbalance further disrupted epigenetic regulation, thereby exacerbating AD-related pathological processes. Using structure-based screening and co-crystallization analysis, we identified Kinsenoside (KIN), a natural small molecule, as a selective competitive inhibitor of IDH1 that binds to its isocitrate-binding pocket. Targeting IDH1 with KIN inhibited its activity, which restored intracellular citrate distribution, reactivated mitochondrial TCA cycle flux, and reestablished metabolic homeostasis. Notably, this intervention not only attenuated neuroinflammation but also reduced beta-amyloid (Abeta) deposition and significantly improved cognitive performance in 5xFAD mice. Collectively, our findings establish IDH1-mediated metabolic dysregulation as a pivotal pathogenic mechanism in AD and highlight KIN as a promising therapeutic candidate by targeting microglial IDH1 to restore metabolic and functional homeostasis.