Amyloid-β-Induced Dysregulation of AMPA Receptor Trafficking

Figure 1

Signaling mechanisms involved in Aβ-induced AMPAR internalization. Soluble Aβ oligomers activate ionotropic NMDA (iNMDA) and metabotropic glutamate (mGlu) receptors, leading to an increase in intracellular . subsequently activates a number of signal transduction cascades involving protein phosphatases (calcineurin, PP1, and STEP₆₁) and protein kinases (Cdk5, PKC, and GSK3β) to modulate the phosphorylation of AMPAR subunits, as well as intracellular signaling and scaffolding molecules. Activation of these pathways, which are commonly shared with LTD, promotes AMPAR internalization and synaptic depression. The cross talk between NMDAR and mGluR5 signaling can be modulated by factors such as Fyn, CaMKII, PKC, and STEP₆₁. The involvement of metabotropic NMDARs in mediating the neurotoxic effects of Aβ, which do not involve the flux of , has recently been proposed, albeit this remains controversial. Dotted arrows indicate events that are inferred from the study of LTD and have not been shown to be directly involved in Aβ-mediated signaling. Thicker lines indicate common pathways, while colored boxes indicate potential therapeutics targets for AD.