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Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer’s disease


Rupawala, Huzefa; Shah, Keshvi; Davies, Caitlin; Rose, Jamie; Colom-Cadena, Marti; Peng, Xianhui; Granat, Lucy; Aljuhani, Manal; Mizuno, Keiko; Troakes, Claire; Perez-Nievas, Beatriz Gomez; Morgan, Alan; So, Po-Wah; Hortobágyi, Tibor; Spires-Jones, Tara L; Noble, Wendy; Giese, Karl Peter (2022). Cysteine string protein alpha accumulates with early pre-synaptic dysfunction in Alzheimer’s disease. Brain Communications, 4(4):fcac192.

Abstract

In Alzheimer’s disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer’s disease are not well understood. In the hippocampus, alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synaptophysin, suggesting that it is a very sensitive marker of synapse degeneration in Alzheimer’s. Here, we identify putative extracellular accumulations of cysteine string alpha protein, which are proximal to beta-amyloid deposits in post-mortem human Alzheimer’s brain and in the brain of a transgenic mouse model of Alzheimer’s disease. Cysteine string protein alpha, at least some of which is phosphorylated at serine 10, accumulates near the core of beta-amyloid deposits and does not co-localize with hyperphosphorylated tau, dystrophic neurites or glial cells. Using super-resolution microscopy and array tomography, cysteine string protein alpha was found to accumulate to a greater extent than other pre-synaptic proteins and at a comparatively great distance from the plaque core. This indicates that cysteine string protein alpha is most sensitive to being released from pre-synapses at low concentrations of beta-amyloid oligomers. Cysteine string protein alpha accumulations were also evident in other neurodegenerative diseases, including some fronto-temporal lobar dementias and Lewy body diseases, but only in the presence of amyloid plaques. Our findings are consistent with suggestions that pre-synapses are affected early in Alzheimer’s disease, and they demonstrate that cysteine string protein alpha is a more sensitive marker for early pre-synaptic dysfunction than traditional synaptic markers. We suggest that cysteine string protein alpha should be used as a pathological marker for early synaptic disruption caused by beta-amyloid.

Abstract

In Alzheimer’s disease, synapse loss causes memory and cognitive impairment. However, the mechanisms underlying synaptic degeneration in Alzheimer’s disease are not well understood. In the hippocampus, alterations in the level of cysteine string protein alpha, a molecular co-chaperone at the pre-synaptic terminal, occur prior to reductions in synaptophysin, suggesting that it is a very sensitive marker of synapse degeneration in Alzheimer’s. Here, we identify putative extracellular accumulations of cysteine string alpha protein, which are proximal to beta-amyloid deposits in post-mortem human Alzheimer’s brain and in the brain of a transgenic mouse model of Alzheimer’s disease. Cysteine string protein alpha, at least some of which is phosphorylated at serine 10, accumulates near the core of beta-amyloid deposits and does not co-localize with hyperphosphorylated tau, dystrophic neurites or glial cells. Using super-resolution microscopy and array tomography, cysteine string protein alpha was found to accumulate to a greater extent than other pre-synaptic proteins and at a comparatively great distance from the plaque core. This indicates that cysteine string protein alpha is most sensitive to being released from pre-synapses at low concentrations of beta-amyloid oligomers. Cysteine string protein alpha accumulations were also evident in other neurodegenerative diseases, including some fronto-temporal lobar dementias and Lewy body diseases, but only in the presence of amyloid plaques. Our findings are consistent with suggestions that pre-synapses are affected early in Alzheimer’s disease, and they demonstrate that cysteine string protein alpha is a more sensitive marker for early pre-synaptic dysfunction than traditional synaptic markers. We suggest that cysteine string protein alpha should be used as a pathological marker for early synaptic disruption caused by beta-amyloid.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Psychiatry and Mental Health
Life Sciences > Biological Psychiatry
Life Sciences > Cellular and Molecular Neuroscience
Life Sciences > Neurology
Uncontrolled Keywords:General Medicine
Language:English
Date:4 July 2022
Deposited On:21 Feb 2023 14:20
Last Modified:28 Feb 2024 02:53
Publisher:Oxford University Press
ISSN:2632-1297
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/braincomms/fcac192
PubMed ID:35928052
Project Information:
  • : FunderKing’s College London
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  • : FunderUK Dementia Research Institute
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  • : FunderUK DRI Ltd
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  • : FunderUK Medical Research Council
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  • : FunderAlzheimer Society
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  • : FunderAlzheimer’s Research UK
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  • : FunderEuropean Research Council
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  • : FunderH2020
  • : Grant ID681181
  • : Project TitleALZSYN - Imaging synaptic contributors to dementia
  • : FunderWellcome Trust Translational Neuroscience
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  • : FunderMedical Research Council
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  • : FunderAlzheimer’s Research UK
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  • : FunderAlzheimer Society
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  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)