The core pathological mechanism of AD manifests as Aβ-Tau toxic synergy (red module) (IMAGE)
Caption
Aberrant cleavage of APP by β/γ-secretases generates Aβ42/43, which is deposited and directly binds mitochondrial VDAC/ATP synthase to inhibit the respiratory chain, causing ATP depletion and ROS burst. Concurrently, hyperphosphorylated tau forms NFTs, disrupting microtubule structure and blocking mitochondrial transport while activating GSK-3β to amplify ROS production. This creates a self-reinforcing loop—Aβ activates GSK-3β to promote tau phosphorylation, while tau aggregation reciprocally enhances Aβ deposition. In signaling pathway dysregulation (blue module), PI3K-Akt pathway suppression releases GSK-3β (exacerbating tau pathology) and collapses glucose metabolism; MAPK hyperactivation (ERK-mediated VDAC phosphorylation damaging mitochondria, JNK/p38 triggering apoptosis/neuroinflammation) combines with GSK-3β-driven mitochondrial fission via Drp1 phosphorylation. Genetic–epigenetic dysregulation (purple module) involves APP/PS mutations and the APOE4 allele that promotes Aβ overproduction/deposition, DNA hypomethylation/aberrant histone modifications that causes pathological protein accumulation, and miRNA imbalance that worsens mitochondrial gene dysfunction. Through cross-module cascades, ROS bursts activate MAPK pathways to disrupt calcium homeostasis, while PI3K-Akt inhibition-induced energy crisis and epigenetic abnormalities synergistically amplify Aβ/Tau toxicity, ultimately forming an irreversible neurodegenerative pathological network.
Credit
Tingting Liu, Zongting Rong, Jingwen Li, Haojie Wu, Jianshe Wei
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