Age-dependent shift of AMPA receptors from synapses to intracellular compartments in Alzheimer´s disease: Immunocytochemical analysis of the CA1 hippocampal region in APP/PS1 transgenic mouse model

Alejandro Martín-Belmonte, Carolina Aguado, Rocío Alfaro-Ruíz, Makoto Itakura, Ana Esther Moreno-Martínez, Luis de la Ossa, Elek Molnar, Yugo Fukazawa, Rafael Luján*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

Synapse loss occurs early in Alzheimer´s disease (AD) patients and animal models. Alterations at synaptic level are a major morphological correlate of the memory deficits and related symptoms of AD. Given the predominant roles of synaptic AMPA receptors (AMPARs) in excitatory synaptic transmission in the brain, changes in their dynamic regulation are also implicated in the pathophysiology of AD. Here, we used immunolocalisation techniques to analyse the expression and subcellular distribution of AMPARs in the hippocampal region of APP/PS1 mouse model of AD. Immunoblots and histoblots revealed that the total amount of AMPARs and their regional expression pattern in the hippocampus was similar in APP/PS1 mice and in age-matched wild type mice. At the ultrastructural level, two synapse populations were examined using SDS-digested freeze-fracture replica labelling in the stratum radiatum in mice: i) on spines of CA1 pyramidal cells; and ii) on randomly found dendritic shafts of CA1 interneurons. While one- and six-months-old APP/PS1 mice exhibited no change, we observed a significant reduction at 12 months in AMPAR density at synapses in both pyramidal cells and interneurons, compared to wild-type. This reduction of AMPARs in dendritic spines was accompanied by a significant increase in AMPAR subunit proteins identified in intracellular compartments. Our data demonstrate an age-dependent reduction of synaptic AMPARs in APP/PS1 mice, which may contribute to impaired learning and memory at later stages of AD.
Original languageEnglish
Article number577996
Number of pages17
JournalFrontiers in Aging Neuroscience
Volume12
DOIs
Publication statusPublished - 6 Oct 2020

Keywords

  • Alzheimer´s disease;
  • hippocampus
  • AMPA receptors
  • immunohistochemistry
  • electron microscopy
  • SDS-digested freeze-fracture replica labelling;
  • AD mouse model
  • human tissue

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