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Cited by 398Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses

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Almeida, Claudia G., Tampellini, Davide, Takahashi, Reisuke H., Greengard, Paul, Lin, Michael T., Snyder, Eric M., Gouras, Gunnar K.·2005·Neurobiology of Disease
DOI 10.1016/j.nbd.2005.02.008
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Abstract

Synaptic dysfunction is increasingly viewed as an early manifestation of Alzheimer's disease (AD), but the cellular mechanism by which beta-amyloid (Abeta) may affect synapses remains unclear. Since cultured neurons derived from APP mutant transgenic mice secrete elevated levels of Abeta and parallel the subcellular Abeta accumulation seen in vivo, we asked whether alterations in synapses occur in this setting. We report that cultured Tg2576 APP mutant neurons have selective alterations in pre- and post-synaptic compartments compared to wild-type neurons. Post-synaptic compartments appear fewer in number and smaller, while active pre-synaptic compartments appear fewer in number and enlarged. Among the earliest changes in synaptic composition in APP mutant neurons were reductions in PSD-95, a protein involved in recruiting and anchoring glutamate receptor subunits to the post-synaptic density. In agreement, we observed early reductions in surface expression of glutamate receptor subunit GluR1 in APP mutant neurons. We provide evidence that Abeta is specifically involved in these alterations in synaptic biology, since alterations in PSD-95 and GluR1 are blocked by gamma-secretase inhibition, and since exogenous addition of synthetic Abeta to wild-type neurons parallels changes in synaptic PSD-95 and GluR1 observed in APP mutant neurons.

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Crossref · 10.1016/j.nbd.2005.02.008

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  • Intraneuronal Aβ buildup has been associated with reduced expression of synaptic proteins.

    “A number of studies have associated intraneuronal Ab buildup with hyperphosphorylation of tau protein, 8 disturbed protein trafficking and sorting, 9 reduced expression of synaptic proteins, 10 and mitochondrial dysfunction.11,12”

    From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [10]

  • APP mutant neurons show differential alterations in synaptic proteins resembling those in AD brain, including early loss of synaptophysin and PSD-95.

    “Remarkably, APP mutant neurons showed differential alterations in synaptic proteins [3] that resembled those that have been described in AD brain, such as early loss of the pre-synaptic protein synaptophysin [113, 163, 192] and the post-synaptic protein PSD-95 [63].”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [3]

  • Exogenous application of Aβ alters synaptic plasticity and important synaptic proteins.

    “Many in vitro and in vivo studies have shown that exogenous application of Aβ alters synaptic plasticity [170, 198] and important synaptic proteins [3, 79, 177], although how precisely this occurs remains unclear.”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [3]

  • AMPA glutamate receptor subunits are among the earliest and most significantly Aβ-altered synaptic proteins.

    “It is of interest that among the earliest and most significantly Aβ-altered synaptic proteins are AMPA glutamate receptor subunits [3, 79], that are particularly important for synaptic plasticity.”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [3]

  • Alterations of extracellular Aβ on selective synaptic proteins mirror those from intraneuronal Aβ accumulation.

    “In addition, alterations of extracellular Aβ on selective synaptic proteins mirrored those from intraneuronal Aβ accumulation [3].”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [3]

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Authors
Almeida, C. G., Tampellini, D., Takahashi, R. H., Greengard, P., Lin, M. T., Snyder, E. M., & Gouras, G. K.
Affiliations
  • Cornell University (US)
  • Rockefeller University (US)
Corresponding author
Gouras, Gunnar K.
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2005-11
Volume
20
Issue
2
Pages
187-198
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2005.02.008
OpenAlex
W2011335492
Cited by
397
References
44
Citations by year
2026: 10 · 2025: 11 · 2024: 14 · 2023: 13 · 2022: 23 · 2021: 23 · 2020: 25 · 2019: 14 · 2018: 15 · 2017: 21 · 2016: 18 · 2015: 16 · 2014: 20 · 2013: 12 · 2012: 27
FWCI
11.19
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Instituto Nacional de Ciência e Tecnologia para Excitotoxicidade e Neuroproteção
  • National Institutes of Health (AG09464, NS002037, NS045677)
  • Alzheimer's Association
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta, Tg2576 mice, PSD-95, GluR1, synaptic dysfunction, Alzheimer's disease, postsynaptic density, gamma-secretase inhibition, cultured neurons
MeSH terms
Disks Large Homolog 4 Protein, Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Enzyme Inhibitors, Membrane Proteins, Mice, Transgenic, Mutation, Synaptic Transmission, Endopeptidases, Synapses, Synaptic Membranes, Down-Regulation, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Receptors, AMPA, Intracellular Signaling Peptides and Proteins, Dendritic Spines, Mice, Guanylate Kinases, Amyloid Precursor Protein Secretases

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