Exendin-4 promotes the membrane trafficking of the AMPA receptor GluR1 subunit and ADAM10 in the mouse neocortex.

Abstract

Glucagon-like peptide-1 (GLP-1) is a novel treatment modality for type 2 diabetes mellitus. However, GLP-1 has been suggested as a therapeutic target for Alzheimer's disease (AD). In rodent studies, GLP-1 reduces amyloid beta (Aβ) and facilitates synaptic plasticity. Therefore, in the present study, we investigated how GLP-1 facilitates synaptic plasticity and reduces the Aβ in vivo. Exendin-4, a GLP-1 receptor agonist that can cross the blood brain barrier, was subcutaneously administered to adult mice. We then extracted the total and the plasma membrane proteins from the mouse neocortex. Exendin-4 significantly increased the phosphorylation level of cAMP response element-binding protein (CREB). Consistently, the expression level of brain-derived neurotrophic factor (BDNF), a transcriptional target of CREB, was increased. Furthermore, exendin-4 increased the membrane protein level of the AMPA receptor GluR1 subunit and postsynaptic density protein-95 (PSD-95), whereas GluR2 was unaffected. These exendin-4-dependent increases in membrane GluR1, total PSD-95 and BDNF were abrogated by pretreatment with temozolomide (TMZ), a DNA-alkylating agent, indicating that these alterations were dependent on exendin-4-induced transcriptional activity. In addition, we found that exendin-4 increased the level of the α-C terminal fragment (α-CTF) of amyloid precursor protein (APP). Furthermore, protein levels of both mature and immature ADAM10, the α-secretase of APP in the plasma membrane, were increased, whereas the total mature and immature ADAM10 levels were unchanged. These exendin-4-dependent increases in α-CTF and ADAM10 were not affected by TMZ. These findings suggested that GLP-1 facilitates the GluR1 membrane insertion through CREB activation and increases α-secretase activity through ADAM10 membrane trafficking. Upregulation of GluR1 and ADAM10 at the plasma membrane were also observed in mice with intracerebroventricular administration of Aβ oligomer, indicating that a part of benefit of exendin-4 against AD may depend on the GluR1 and ADAM10 membrane trafficking.

• Authors: Nobuaki Ohtake, Mieko Saito, Masaaki Eto, Kenjiro Seki
• Journal: Regulatory peptides (Regul Pept) Vol. 190-191 Pg. 1-11 (May 2014) ISSN: 1873-1686 [Electronic] Netherlands
• PMID: 24769307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Membrane Proteins
• Peptides
• Receptors, AMPA
• Venoms
• Exenatide
• Amyloid Precursor Protein Secretases
• ADAM Proteins
• ADAM10 Protein
• Adam10 protein, mouse
• glutamate receptor ionotropic, AMPA 1

Topics

• ADAM Proteins (metabolism)
• ADAM10 Protein
• Amyloid Precursor Protein Secretases (metabolism)
• Animals
• Cell Membrane (drug effects, metabolism)
• Exenatide
• Infusions, Intraventricular
• Male
• Membrane Proteins (metabolism)
• Mice
• Neocortex (cytology, drug effects)
• Peptides (administration & dosage, pharmacology)
• Receptors, AMPA (metabolism)
• Venoms (administration & dosage, pharmacology)