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Figure 1 | Molecular Neurodegeneration

Figure 1

From: Synaptic dysfunction and septin protein family members in neurodegenerative diseases

Figure 1

Schematic representation of specific synaptic alterations induced by excess accumulation of soluble Aβ. Aβ is produced from APP through sequential cleavages by BACE1 and γ-secretase at the presynaptic site and released to the synaptic cleft. Increased Aβ accumulation results in the internalization of AMPAR from the postsynaptic membrane, possibly via caspase-3-Akt1-GSK3β or altered LRP6-mediated Wnt signaling. Aβ may induce activation of extrasynaptic NMDAR (eNMDAR), due to faulty EAAT1/2-mediated regulation of glutamate levels by astrocytes, leading to the activation induction of downstream RNS/ROS-mediated neurodegenerative events. Additionally, Aβ accumulation induces tau localization to postsynaptic sites, resulting in the postsynaptic recruitment of Src kinase Fyn. Aβ is also proposed to activate histone deacetylase 2, resulting in the suppressed expression of genes required for synaptic function and stability, such as BDNF, Cdk5, Homer1, NLGN1, Syp, GluR1, GluR2, NR2A, NR2B, and STIM2. Abbreviations: Brain-derived neurotrophic factor (BDNF), Cyclin-dependent kinase 5 (CDK5), Homer homolog 1 (Homer1), Neuroligin 1 (NLGN1), Synaptophysin (Syp), Glutamate receptor 1 (GluR1), Glutamate receptor 2 (GluR2), N-mehtyl-D-Aspartate 2A (NR2A), N-mehtyl-D-Aspartate 2B (NR2B), Stromal interaction molecule 2 (STIM2).

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