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Clusterin accumulates in synapses in Alzheimer’s disease and is increased in apolipoprotein E4 carriers

Jackson, Rosemary J, Rose, Jamie, Tulloch, Jane, Henstridge, Chris, Smith, Colin, Spires-Jones, Tara L·2019·Brain Communications
DOI 10.1093/braincomms/fcz003PMC PMC6904249
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Abstract

One of the major challenges in developing effective therapeutic strategies for Alzheimer’s disease is understanding how genetic risk factors contribute to neurodegeneration. The apolipoprotein epsilon 4 isoform (APOE4) and variants in the Clusterin (CLU) gene (also known as apolipoprotein J) are associated with increased risk of developing Alzheimer’s. Our previous work demonstrated that APOE4 exacerbates synapse degeneration and synaptic accumulation of toxic oligomeric amyloid beta in human Alzheimer’s and mouse models of disease. Here, we observe clusterin in synapses in human Alzheimer's disease brain. The percentage of synapses containing clusterin is higher in APOE4 carriers than APOE3 carriers. Furthermore, we observe oligomeric amyloid beta accumulation within synapses containing clusterin which is also higher in APOE4 carriers. These data link two genetic risk factors with synapse degeneration in Alzheimer’s and support a potential role for clusterin working with APOE in causing synaptic damage.

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Crossref · 10.1093/braincomms/fcz003

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  • Aβ can be found in synapses of Alzheimer's cases.

    “It has been shown that Aβ can be found in synapses of Alzheimer’s cases [6, 29, 34, 51, 65, 66], but the mechanisms by which Aβ induces synaptic toxicity remain unclear.”

    From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [29]

  • Sample sizes were based on power calculations using effect size of 0.79 from previous human array tomography studies looking at colocalization of clusterin and Aβ in synapses in Alzheimer's, indicating that n = 6 per group is sufficient at power = 0.8 to detect a difference between colocalization of proteins at synapses between AD and controls.

    “Sample sizes were based on power calculations using effect size of 0.79 from our previous human array tomography studies looking at colocalization of clusterin and Aβ in synapses in Alzheimer’s [29] indicating that n = 6 per group is sufficient at power = 0.8 to detect a difference between colocalization of proteins at synapses between AD and controls (calculated using the WebPower package in R 4.”

    From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [29]

  • In AD cases, images were acquired with a plaque in the field since our previous work demonstrated that synaptic Aβ accumulation is most prominent around plaques.

    “In AD cases, images were acquired with a plaque in the field since our previous work demonstrated that synaptic Aβ accumulation is most prominent around plaques [29, 34].”

    From Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease (2024) · cites this paper as [29]

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Citations

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Research works printed but not linked: 27

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Metadata

Authors
Jackson, R. J., Rose, J., Tulloch, J., Henstridge, C., Smith, C., & Spires-Jones, T. L.
Affiliations
  • Centre for Discovery Brain Sciences, UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
  • Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
ORCID
Spires-Jones, Tara L
Venue
Brain Communications
Publisher
Oxford University Press (OUP)
Published
2019-01-01
Volume
1
Issue
1
ISSN
2632-1297
DOI
10.1093/braincomms/fcz003
PMC
PMC6904249
Cited by
69
References
5
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor, 174 d)
Funders
  • European Research Council
  • Wellcome Trust
  • Medical Research Council
  • Alzheimer’s Society and Alzheimer’s Research UK

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