期刊
FRONTIERS IN AGING NEUROSCIENCE
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnagi.2020.577996
关键词
AD mouse model; hippocampus; electron microscopy; AMPA receptors; Alzheimer's disease
资金
- European Union's Horizon 2020 Framework Programme for Research and Innovation [785907]
- Spanish Ministerio de Economia y Competitividad [RTI2018-095812-B-I00]
- Junta de Comunidades de Castilla-La Mancha [SBPLY/17/180501/000229]
- Life Science Innovation Center (Research and Education Program for Life Science) at University of Fukui
- JSPS KAKENHI [16H04662, 17K19446, 18H05120]
- Biotechnology and Biological Sciences Research Council [BB/J015938/1]
- Innovate UK (UK Research and Innovation) Knowledge Transfer Partnership Grant [12333]
- BBSRC [BB/J015938/1] Funding Source: UKRI
- Grants-in-Aid for Scientific Research [17K19446, 18H05120, 16H04662] Funding Source: KAKEN
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 immunolocalization techniques to analyze 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 labeling in thestratum radiatumin mice: (i) on spines of CA1 pyramidal cells; and (ii) on randomly found dendritic shafts of CA1 interneurons. While 1- and 6-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.
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