fig1

Figure 1. Deposition of Aβ and the process of interaction with p-tau. In the non-amyloidogenic processing pathway, APP is cleaved by α-secretase and γ-secretase, ultimately generating non-toxic soluble fragments (such as sAPPα and P3); In the amyloidogenic processing pathway, APP is cleaved by β-secretase and processed by γ-secretase to produce Aβ peptides. Aβ activates CDK-5 and GSK-3β, accelerating tau hyperphosphorylation. Phosphorylated tau activates Fyn kinase, which assembles with NR2B to form NMDAR receptors. Their activation induces calcium influx, disrupts mitochondrial balance, generates excessive ROS, and ultimately triggers cell apoptosis; Aβ leads to the sustained loss of dendritic spines and glutamatergic synapses by reducing the activation of NMDARs or enhancing the activation of NMDAR-dependent calcineurin. Aβ: β-amyloid; p-tau: hyperphosphorylated tau; APP: amyloid precursor protein; sAPPα: secreted amyloid precursor protein alpha; P3: amyloid β-peptide 17-40/42; CDK-5: cyclin-dependent kinase 5; GSK-3β: glycogen synthase kinase-3β; NR2B: glutamate ionotropic receptor NMDA type subunit 2B; NMDAR: N-methyl-D-aspartate receptor; ROS: reactive oxygen species; AICD: amyloid precursor protein intracellular domain; PSD95: postsynaptic density protein 95; NADH: nicotinamide adenine dinucleotide, reduced form; ATP: adenosine triphosphate; NFT: neurofibrillary tangle.