Endophilin2 Interacts with GluA1 to Mediate AMPA Receptor Endocytosis Induced by Oligomeric Amyloid-β

Abstract

Amyloid-β (Aβ) plays an important role in Alzheimer's disease (AD), as oligomeric Aβ induces loss of postsynaptic AMPA receptors (AMPARs) leading to cognitive deficits. The loss of postsynaptic AMPARs is mediated through the clathrin-dependent endocytosis pathway, in which endophilin2 is one of the important regulatory proteins. Endophilin2, which is enriched in both the pre- and postsynaptic membrane, has previously been reported to be important for recycling of synaptic vesicles at the presynaptic membrane. However, the role of endophilin2 in oligomeric Aβ-induced postsynaptic AMPAR endocytosis is not well understood. In this study, we show that endophilin2 does not affect constitutive AMPAR endocytosis. Endophilin2 knockdown, but not overexpression, resisted oligomeric Aβ-induced AMPAR dysfunction. Moreover, endophilin2 colocalized and interacted with GluA1, a subunit of AMPAR, to regulate oligomeric Aβ-induced AMPAR endocytosis. Thus, we have determined a role of endophilin2 in oligomeric Aβ-induced postsynaptic AMPAR dysfunction, indicating possible directions for preventing the loss of AMPARs in cognitive impairment and providing evidence for the clinical treatment of AD.

Molecular mechanism of Fast Endophilin-Mediated Endocytosis

“…The binding of VGLUT1 to Endophilin recruits the transporter to a fast endocytic pathway and synaptic vesicle recycling, thereby regulating neurotransmitter release and short-term plasticity [88,90]. Endophilin also binds to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, either directly to the GluA1, but not GluA2 subunit, or through the adaptor Arc/Arg3.1 [91][92][93] (Table 1). The absence of Arc or Endophilin reduces AMPAR uptake and increases cell surface levels of the receptor, thereby affecting postsynaptic neuron plasticity and long-term depression.…”

Spastin Interacts with CRMP5 to Promote Neurite Outgrowth by Controlling the Microtubule Dynamics

“…All constructs were verified by sequencing. A detailed description of the methods used for constructing cDNA plasmids is available in previous reports Zhang et al, 2017). Validated spastin siRNA (si-spastin) fragments (5′-CCAGUCAGAUGAGAAAUAUTT-3′) and a negative control (NC; a scrambled sequence) were synthesized by Shanghai GenePharma Co. Ltd. (Shanghai, China).…”

Collapsin Response Mediator Protein 2 and Endophilin2 Coordinate Regulation of AMPA Receptor GluA1 Subunit Recycling

“…All experiments were repeated independently at least three times. Zhang et al, 2017;Abe et al, 2018). Moreover, our results showed that CRMP2 interacted with endophilin2; hence, we hypothesized that the interaction between CRMP2 and endophilin2 may influence synaptic AMPAR levels.…”

“…Additionally, our results confirmed that CRMP2 was bound to the SH3 domain of endophilin2 through its C-terminus (Figure 2). In previous studies, endophilin2 has been shown to colocalize with PSD95, suggesting that this protein may be abundantly expressed in postsynaptic regions (Chowdhury et al, 2006;Zhang et al, 2017). Moreover, endophilin2 has also been shown colocalize with GluA1, thereby regulating AMPAR trafficking (Zhang et al, 2017).…”

“…Moreover, the early onset gene Arc/Arg3.1 interacts with endophilin2/3 and dynamin and enhances receptor endocytosis (Chowdhury et al, 2006). In our previous study, we found that endophilin2 interacted directly with the C-terminus of the GluA1 subunit, but not the GluA2 subunit, to mediate oligomeric amyloid-β-induced AMPAR endocytosis (Zhang et al, 2017). Although the role of endophilin in regulating AMPAR endocytosis is known, the fate of the receptor after undergoing endocytosis by endophilin is unclear.…”