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Cited by 137Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The amyloid plaque proteome in early onset Alzheimer’s disease and Down syndrome

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Drummond, Eleanor, Kavanagh, Tomas, Pires, Geoffrey, Marta-Ariza, Mitchell, Kanshin, Evgeny, Nayak, Shruti, Faustin, Arline, Berdah, Valentin +2 more·2022·Acta Neuropathologica Communications
DOI 10.1186/s40478-022-01356-1PMC PMC9008934

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Abstract

Amyloid plaques contain many proteins in addition to beta amyloid (Aβ). Previous studies examining plaque-associated proteins have shown these additional proteins are important; they provide insight into the factors that drive amyloid plaque development and are potential biomarkers or therapeutic targets for Alzheimer’s disease (AD). The aim of this study was to comprehensively identify proteins that are enriched in amyloid plaques using unbiased proteomics in two subtypes of early onset AD: sporadic early onset AD (EOAD) and Down Syndrome (DS) with AD. We focused our study on early onset AD as the drivers of the more aggressive pathology development in these cases is unknown and it is unclear whether amyloid-plaque enriched proteins differ between subtypes of early onset AD. Amyloid plaques and neighbouring non-plaque tissue were microdissected from human brain sections using laser capture microdissection and label-free LC–MS was used to quantify the proteins present. 48 proteins were consistently enriched in amyloid plaques in EOAD and DS. Many of these proteins were more significantly enriched in amyloid plaques than Aβ. The most enriched proteins in amyloid plaques in both EOAD and DS were: COL25A1, SMOC1, MDK, NTN1, OLFML3 and HTRA1. Endosomal/lysosomal proteins were particularly highly enriched in amyloid plaques. Fluorescent immunohistochemistry was used to validate the enrichment of four proteins in amyloid plaques (moesin, ezrin, ARL8B and SMOC1) and to compare the amount of total Aβ, Aβ40, Aβ42, phosphorylated Aβ, pyroglutamate Aβ species and oligomeric species in EOAD and DS. These studies showed that phosphorylated Aβ, pyroglutamate Aβ species and SMOC1 were significantly higher in DS plaques, while oligomers were significantly higher in EOAD. Overall, we observed that amyloid plaques in EOAD and DS largely contained the same proteins, however the amount of enrichment of some proteins was different in EOAD and DS. Our study highlights the significant enrichment of many proteins in amyloid plaques, many of which may be potential therapeutic targets and/or biomarkers for AD.

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  • A previous report found no significant difference in the abundance of APOE in amyloid-β plaques in the hippocampus and surrounding entorhinal/temporal cortex, from cases of DSAD and EOAD.

    “However, a previous report found no significant difference in the abundance of APOE in amyloid-β plaques in the hippocampus and surrounding entorhinal/temporal cortex, from cases of DSAD and EOAD [13].”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [13]

    The Results section, “Proteins enriched in plaques in both EOAD and DS” (page unavailable), identifies APOE as one of the most abundant plaque proteins in both groups. The Methods section, “Laser capture microdissection for localized proteomics” (page unavailable), says plaques were sampled from hippocampal sections that included entorhinal and temporal cortex. Our copy does not report an APOE-specific test showing no significant difference in abundance between DS and EOAD plaques; the reported correlation across plaque proteins does not establish that result. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • APOE is sequestered in amyloid-β plaques within the brain, including in individuals with DSAD.

    “Previous studies have shown that APOE is sequestered in amyloid-β plaques within the brain, including in individuals with DSAD [3, 13], similar to what we have observed (Supplementary Fig. 9).”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [13]

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Authors
Drummond, E., Kavanagh, T., Pires, G., Marta-Ariza, M., Kanshin, E., Nayak, S., Faustin, A., Berdah, V., Ueberheide, B., & Wisniewski, T.
Affiliations
  • The University of Sydney (AU)
  • New York University (US)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Corresponding author
Drummond, Eleanor
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2022-04-13
Volume
10
Issue
1
Pages
53-53
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-022-01356-1
PMC
PMC9008934
OpenAlex
W4226136981
Cited by
137
References
149
Citations by year
2026: 17 · 2025: 41 · 2024: 39 · 2023: 36 · 2022: 4
FWCI
18.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (AF056850, AG066512, AG056850, AG060882)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid plaques, early-onset Alzheimer's disease, Down syndrome, amyloid-beta, SMOC1, Arl8b, moesin, ezrin, pyroglutamate amyloid-beta, amyloid-beta oligomers, therapeutic target, biomarkers
MeSH terms
High-Temperature Requirement A Serine Peptidase 1, Alzheimer Disease, Brain, Down Syndrome, Glycoproteins, Humans, Pyrrolidonecarboxylic Acid, Amyloid beta-Peptides, Proteome, Intercellular Signaling Peptides and Proteins, Plaque, Amyloid

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