The core pathological network of AD is formed by a triangular cyclic system composed of mitochondrial dysfunction, metabolic disturbances, and calcium homeostasis imbalance, which interact bidirectionally to create a self-reinforcing vicious cycle. (IMAGE)
Caption
Mitochondrial dysfunction manifests as structural damage (swelling, cristae rupture, increased volume/decreased numerical density), energy metabolism abnormalities (reduced COX and Complex I-III activities, elevated lactate/decreased succinate), dynamic imbalance (DRP1 up-regulation/OPA1 down-regulation leading to fragmentation), and autophagy impairment (Aβ-mediated inhibition of PINK1/Parkin), collectively triggering the ATP crisis and ROS accumulation.
Metabolic disturbances form a glucose–lipid–amino acid triad of dysregulation: impaired glucose metabolism involves GLUT1/3 suppression and compensatory glycolysis elevation, exacerbating mitochondrial damage through feedback inhibition; lipid abnormalities drive Aβ deposition via cholesterol accumulation, ApoE4 effects, and membrane fluidity reduction; and amino acid imbalance features glutamate/GABA ratio disruption and ammonia toxicity. Calcium dyshomeostasis arises from NMDA receptor/IP3R hyperactivation, inducing a calcium overload that activates proteases, triggers ROS bursts, promotes tau phosphorylation→NFT formation, and collapses the mitochondrial membrane potential. These three systems interact through positive feedback loops—ROS→mtDNA mutations→ETC damage, Aβ→GLUT inhibition→energy crisis, and calcium overload→mitochondrial permeability transition pore opening. ATP depletion and defective autophagy further transform damaged mitochondria into persistent ROS sources, ultimately driving an irreversible neurodegenerative cascade.
Credit
Tingting Liu, Zongting Rong, Jingwen Li, Haojie Wu, Jianshe Wei
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