Cited by 31Prion Diseases and Protein MisfoldingAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Analysis of the Hippocampal Proteome in ME7 Prion Disease Reveals a Predominant Astrocytic Signature and Highlights the Brain-restricted Production of Clusterin in Chronic Neurodegeneration

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Asuni, Ayodeji A., Gray, Bryony, Bailey, Joanne, Skipp, Paul, Perry, V. Hugh, O'Connor, Vincent·2014·Journal of Biological Chemistry

Abstract

Prion diseases are characterized by accumulation of misfolded protein, gliosis, synaptic dysfunction, and ultimately neuronal loss. This sequence, mirroring key features of Alzheimer disease, is modeled well in ME7 prion disease. We used iTRAQ(TM)/mass spectrometry to compare the hippocampal proteome in control and late-stage ME7 animals. The observed changes associated with reactive glia highlighted some specific proteins that dominate the proteome in late-stage disease. Four of the up-regulated proteins (GFAP, high affinity glutamate transporter (EAAT-2), apo-J (Clusterin), and peroxiredoxin-6) are selectively expressed in astrocytes, but astrocyte proliferation does not contribute to their up-regulation. The known functional role of these proteins suggests this response acts against protein misfolding, excitotoxicity, and neurotoxic reactive oxygen species. A recent convergence of genome-wide association studies and the peripheral measurement of circulating levels of acute phase proteins have focused attention on Clusterin as a modifier of late-stage Alzheimer disease and a biomarker for advanced neurodegeneration. Since ME7 animals allow independent measurement of acute phase proteins in the brain and circulation, we extended our investigation to address whether changes in the brain proteome are detectable in blood. We found no difference in the circulating levels of Clusterin in late-stage prion disease when animals will show behavioral decline, accumulation of misfolded protein, and dramatic synaptic and neuronal loss. This does not preclude an important role of Clusterin in late-stage disease, but it cautions against the assumption that brain levels provide a surrogate peripheral measure for the progression of brain degeneration.

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  • Microgliosis and astrocytosis were previously described in the dentate gyrus area of the hippocampus of prion disease mice.

    “Microgliosis and astrocytosis were previously described in the dentate gyrus area of the hippocampus of prion disease mice [32, 38, 39].”

    From Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease (2023) · cites this paper as [39]

    The Results (Fig. 3; page unavailable) show reactive astrocytes in the hippocampus of ME7 prion-disease mice and label the dentate gyrus. The Results also report microglial proliferation during prion disease, but our copy does not establish that microgliosis occurred specifically in the dentate gyrus. (LLM, conf=0.83)

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  1. Gray, B. C., (2006) Evidence for Synaptic Dysfunction in Prion Disease. Ph.D. thesis, School of Biological Sciences, University of Southampton, Southampton, UK,.

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Authors
Asuni, A. A., Gray, B., Bailey, J., Skipp, P., Perry, V. H., & O'Connor, V.
Affiliations
University of Southampton (GB)
Corresponding author
Asuni, Ayodeji A.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2014-02
Volume
289
Issue
7
Pages
4532-4545
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2093306010
Cited by
31
References
112
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2021: 10 · 2020: 2 · 2019: 5 · 2017: 3 · 2016: 1 · 2015: 4 · 2014: 3
FWCI
1.19
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • ePrints Soton (University of Southampton) (acceptedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
hippocampal proteome, clusterin, astrocytes, reactive gliosis, glial fibrillary acidic protein, GLT-1, peroxiredoxin 6, acute phase proteins, neurodegeneration, protein misfolding, blood biomarkers, excitotoxicity, reactive oxygen species
MeSH terms
Alzheimer Disease, Animals, Astrocytes, Disease Models, Animal, Female, Hippocampus, Humans, Nerve Tissue Proteins, Biomarkers, Prion Diseases, Proteome, Clusterin, Mice

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