Ceftriaxone regulates glutamate production and vesicular assembly in presynaptic terminals through GLT-1 in APP/PS1 mice

Copyright © 2021 Elsevier Inc. All rights reserved..

Perturbations in the glutamate-glutamine cycle and glutamate release from presynaptic terminals have been involved in the development of cognitive deficits in Alzheimer's disease (AD) patients and mouse models. Glutamate transporter-1 (GLT-1) removes glutamate from the synaptic cleft and transports it into astrocytes, where it is used as substrate for the glutamate-glutamine cycle. Ceftriaxone has been reported to improve cognitive deficits in AD mice by increasing GLT-1 expression, glutamate transformation to glutamine, and glutamine efflux from astrocytes. However, the impact of ceftriaxone on glutamine metabolism in neurons is unknown. The present study aimed to investigate whether ceftriaxone regulated the production and vesicular assembly of glutamate in the presynaptic terminals of neurons and to determine GLT-1 involvement in this process. We used the amyloid precursor protein (APP)/presenilin-1 (PS1) AD mouse model and GLT-1 knockdown APP/PS1 (GLT-1+/-/APP/PS1) mice. The expression levels of sodium-coupled neutral amino-acid transporter 1 (SNAT1) and vesicular glutamate transporters 1 and 2 (VGLUT1/2) were analyzed by immunofluorescence and immunohistochemistry staining as well as by Western blotting. Glutaminase activity was assayed by fluorometry. Ceftriaxone treatment significantly increased SNAT1 expression and glutaminase activity in neurons in APP/PS1 mice. Similarly, VGLUT1/2 levels were increased in the presynaptic terminals of APP/PS1 mice treated with ceftriaxone. The deletion of one GLT-1 allele in APP/PS1 mice prevented the ceftriaxone-induced upregulation of SNAT1 and VGLUT1/2 expression, indicating that GLT-1 played an important role in ceftriaxone effect. Based on the role of SNAT1, glutaminase, and VGLUT1/2 in the glutamate-glutamine cycle in neurons, the present results suggested that ceftriaxone improved the production and vesicular assembly of glutamate as a neurotransmitter in presynaptic terminals by acting on GLT-1 in APP/PS1 mice.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:183

Enthalten in:

Neurobiology of learning and memory - 183(2021) vom: 01. Sept., Seite 107480

Sprache:

Englisch

Beteiligte Personen:

Fan, ShuJuan [VerfasserIn]
Li, Li [VerfasserIn]
Xian, XiaoHui [VerfasserIn]
Liu, LiRong [VerfasserIn]
Gao, JunXia [VerfasserIn]
Li, WenBin [VerfasserIn]

Links:

Volltext

Themen:

3KX376GY7L
75J73V1629
APP/PS1 mice
APP protein, human
Amino Acid Transport System A
Amyloid beta-Protein Precursor
Anti-Bacterial Agents
Ceftriaxone
EC 3.5.1.2
Excitatory Amino Acid Transporter 2
GLT-1
Glutamic Acid
Glutaminase
Journal Article
PSEN1 protein, human
Presenilin-1
Research Support, Non-U.S. Gov't
SNAT1
Slc17a6 protein, mouse
Slc17a7 protein, mouse
Slc1a2 protein, mouse
Slc38a1 protein, mouse
VGLUT
Vesicular Glutamate Transport Protein 1
Vesicular Glutamate Transport Protein 2

Anmerkungen:

Date Completed 08.02.2022

Date Revised 08.02.2022

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.nlm.2021.107480

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM327008660