Impairment of Tricarboxylic Acid Cycle (TCA) Cycle in Alzheimer's Disease: Mechanisms, Implications, and Potential Therapies

Alzheimer's disease (AD) is a neurodegenerative condition defined by the gradual impairment of cognitive functions, synaptic disarray, and extensive neuronal loss. Emerging evidence suggests that metabolic impairment, specifically within tricarboxylic acid (TCA) cycle, is instrumental in the AD pathophysiology. TCA cycle represents an indispensable pathway in metabolism that is responsible for energy production, and the maintenance of cellular homeostasis, particularly in neurons. Several in vitro, clinical, and in vivo studies reported that several TCA cycle enzymes disrupt during AD. Disruption in TCA cycle enzymes exhibits more pronounced impact on the brain owing to its high metabolic activity and continuous demand for energy, where any reduction in ATP production can severely impair neuronal function, synaptic plasticity, and overall cognitive processes. The current review explores the mechanisms underlying AD related impairment in TCA cycle, focussing on the molecular alterations of TCA enzymes. We also discussed potential activators and inhibitors of TCA cycle enzymes as a potential therapeutic intervention to restore AD related metabolic balance.