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Cited by 357Alzheimer's disease research and treatmentsAdvanced Proteomics Techniques and ApplicationsDementia and Cognitive Impairment Research

Phosphorylated tau interactome in the human Alzheimer's disease brain

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Drummond, Eleanor, Pires, Geoffrey, MacMurray, Claire, Askenazi, Manor, Nayak, Shruti, Bourdon, Marie, Safar, Jiri, Ueberheide, Beatrix +1 more·2020·Brain
DOI 10.1093/brain/awaa223PMC PMC7526722
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Abstract

Accumulation of phosphorylated tau is a key pathological feature of Alzheimer’s disease. Phosphorylated tau accumulation causes synaptic impairment, neuronal dysfunction and formation of neurofibrillary tangles. The pathological actions of phosphorylated tau are mediated by surrounding neuronal proteins; however, a comprehensive understanding of the proteins that phosphorylated tau interacts with in Alzheimer’s disease is surprisingly limited. Therefore, the aim of this study was to determine the phosphorylated tau interactome. To this end, we used two complementary proteomics approaches: (i) quantitative proteomics was performed on neurofibrillary tangles microdissected from patients with advanced Alzheimer’s disease; and (ii) affinity purification-mass spectrometry was used to identify which of these proteins specifically bound to phosphorylated tau. We identified 542 proteins in neurofibrillary tangles. This included the abundant detection of many proteins known to be present in neurofibrillary tangles such as tau, ubiquitin, neurofilament proteins and apolipoprotein E. Affinity purification-mass spectrometry confirmed that 75 proteins present in neurofibrillary tangles interacted with PHF1-immunoreactive phosphorylated tau. Twenty-nine of these proteins have been previously associated with phosphorylated tau, therefore validating our proteomic approach. More importantly, 34 proteins had previously been associated with total tau, but not yet linked directly to phosphorylated tau (e.g. synaptic protein VAMP2, vacuolar-ATPase subunit ATP6V0D1); therefore, we provide new evidence that they directly interact with phosphorylated tau in Alzheimer’s disease. In addition, we also identified 12 novel proteins, not previously known to be physiologically or pathologically associated with tau (e.g. RNA binding protein HNRNPA1). Network analysis showed that the phosphorylated tau interactome was enriched in proteins involved in the protein ubiquitination pathway and phagosome maturation. Importantly, we were able to pinpoint specific proteins that phosphorylated tau interacts with in these pathways for the first time, therefore providing novel potential pathogenic mechanisms that can be explored in future studies. Combined, our results reveal new potential drug targets for the treatment of tauopathies and provide insight into how phosphorylated tau mediates its toxicity in Alzheimer’s disease.

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  • Small quantities of MAP2 have been identified in neurofibrillary tangles.

    “Nevertheless, small quantities of MAP2 have been identified in neurofibrillary tangles (34, 35), and interactome studies in human AD brain have captured MAP2 together with oligomeric tau (35, 36).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [35]

    The ‘Proteome of neurofibrillary tangles in sporadic Alzheimer’s disease’ section reports proteins identified in tangle-containing samples, but the passages retrieved do not identify MAP2 or describe its quantity. Searches for ‘MAP2’ and ‘microtubule-associated protein 2’ did not locate a passage establishing the claim in our copy. (LLM, conf=0.70)

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Authors
Drummond, E., Pires, G., MacMurray, C., Askenazi, M., Nayak, S., Bourdon, M., Safar, J., Ueberheide, B., & Wisniewski, T.
Affiliations
  • The University of Sydney (AU)
  • Centre National de la Recherche Scientifique (FR)
  • New York University (US)
  • Biomedical Hosting LLC, USA
  • NYU Langone Health (US)
  • Case Western Reserve University (US)
  • Centre for Cognitive Neurology, Department of Neurology, New York University School of Medicine, New York, NY, USA
Corresponding author
Drummond, Eleanor
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2020-08-19
Volume
143
Issue
9
Pages
2803-2817
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awaa223
PMC
PMC7526722
OpenAlex
W3078141069
Cited by
357
References
12
Citations by year
2026: 52 · 2025: 76 · 2024: 67 · 2023: 70 · 2022: 53 · 2021: 31 · 2020: 3 · 2019: 2 · 2012: 1
FWCI
23.76
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • Brain (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Bluesand Foundation and Dementia Australia
  • Philippe Chatrier Foundation
  • National Institutes of Health (P30AG066512, P01AG060882, RF1AG058267)
  • NYU School of Medicine
  • NIH (1S10OD010582-01A1)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
phosphorylated tau, Alzheimer's disease, neurofibrillary tangles, protein-protein interaction, ubiquitination, phagosome maturation, VAMP2, hnRNP A1, tauopathy, therapeutic target
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Chromatography, Liquid, Female, Humans, Male, Middle Aged, Phosphorylation, tau Proteins, Proteomics, Tandem Mass Spectrometry

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