Regul Pept. 2014 May;190-191:1-11. doi: 10.1016/j.regpep.2014.04.003.

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

 

Ohtake N1, Saito M1, Eto M1, Seki K2.
  • 1Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan.
  • 2Department of Pharmacology, School of Pharmaceutical Science, Ohu University, 31-1 Misumido, Tomitamachi, Koriyama, Fukushima 963-8611, Japan. Electronic address: k-seki@pha.ohu-u.ac.jp.

 

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. Copyright © 2014 Elsevier B.V.

KEYWORDS: ADAM10; AMPA receptor GluR1 subunit; Exendin-4; Glucagon-like peptide-1; Mouse neocortex

PMID: 24769307

 

 

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