Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice

Morris, Meaghan; Knudsen, Giselle M; Maeda, Sumihiro; Trinidad, Jonathan C; Ioanoviciu, Alexandra; Burlingame, Alma L; Mucke, Lennart

doi:10.1038/nn.4067

Cited by 472Alzheimer's disease research and treatmentsAdvanced Proteomics Techniques and ApplicationsGlycosylation and Glycoproteins Research

Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice

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Morris, Meaghan, Knudsen, Giselle M, Maeda, Sumihiro, Trinidad, Jonathan C, Ioanoviciu, Alexandra, Burlingame, Alma L, Mucke, Lennart·2015·Nature Neuroscience

DOI 10.1038/nn.4067PMC PMC8049446

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Abstract

The microtubule-associated protein tau has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative disorders. Reducing tau levels ameliorates AD-related synaptic, network, and behavioral abnormalities in transgenic mice expressing human amyloid precursor protein (hAPP). We used mass spectrometry to characterize the post-translational modification of endogenous tau isolated from wild-type and hAPP mice. We identified seven types of tau modifications at 63 sites in wild-type mice. Wild-type and hAPP mice had similar modifications, supporting the hypothesis that neuronal dysfunction in hAPP mice is enabled by physiological forms of tau. Our findings provide clear evidence for acetylation and ubiquitination of the same lysine residues; some sites were also targeted by lysine methylation. Our findings refute the hypothesis of extensive O-linked N-acetylglucosamine (O-GlcNAc) modification of endogenous tau. The complex post-translational modification of physiological tau suggests that tau is regulated by diverse mechanisms.

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In healthy neurons, Tau is observed in the dendritic shaft as well as in pre- and post-synaptic structures.
“Interestingly, several recent studies suggest that Tau may directly regulate synaptic function and plasticity: in healthy neurons, Tau is observed in the dendritic shaft as well as in pre- and post-synaptic structures [92, 94, 156].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [94]
The Results (page unavailable) identify tau in postsynaptic-density fractions from wildtype mice, supporting the postsynaptic part of the claim. The paper does not establish tau's presence in dendritic shafts or presynaptic structures in healthy neurons. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Accumulation of ubiquitin-conjugated tau at Lys254, 257, 290, 311, 317 and 353 has been identified in PHF from AD brain and in an AD mouse model.
“Accumulation of ubiquitin-conjugated tau at Lys254, 257, 290, 311, 317 and 353 has been identified in PHF from AD brain and in an AD mouse model [161, 163, 164].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [161]
Tau Arg methylation was identified in normal and AD mouse models.
“Although tau Arg methylation was identified in normal and AD mouse models [161]”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [161]
Tens of possible PTM sites have been described for Tau in in vitro, in vivo AD mouse models, and postmortem human studies.
“Tens of possible PTM sites have been described for Tau in studies involving in vitro (Hanger et al., 2007; Martin et al., 2013a, 2013b) and in vivo AD mouse models (Morris et al., 2015; Tramutola et al., 2018) and in postmortem human studies (Hanger et al., 2007; Min et al., 2015).”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Morris et al., 2015
The extensive interplay observation is partially consistent with recent Tau PTM mapping results in mice.
“an observation partially consistent with recent Tau PTM mapping results in mice (Morris et al., 2015; Table S5).”
From Tau PTM Profiles Identify Patient Heterogeneity and Stages of Alzheimer’s Disease (2020) · cites this paper as Morris et al., 2015

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Authors: Morris, M., Knudsen, G. M., Maeda, S., Trinidad, J. C., Ioanoviciu, A., Burlingame, A. L., & Mucke, L.
Affiliations: Gladstone Institutes (US)
University of California, San Francisco (US)
Corresponding author: Mucke, Lennart
ORCID: Morris, Meaghan
Knudsen, Giselle M
Maeda, Sumihiro
Trinidad, Jonathan C
Burlingame, Alma L
Mucke, Lennart
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2015-07-20
Volume: 18
Issue: 8
Pages: 1183-1189
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/nn.4067
PMC: PMC8049446
OpenAlex: W1032333588
Cited by: 472
References: 68
Citations by year: 2026: 24 · 2025: 30 · 2024: 33 · 2023: 40 · 2022: 36 · 2021: 67 · 2020: 48 · 2019: 43 · 2018: 53 · 2017: 45 · 2016: 47 · 2015: 5
FWCI: 36.81
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institute of General Medical Sciences (GM103481, P41GM103481)
National Institute of Neurological Disorders and Stroke (R01NS041787, NS041787)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
Keywords: tau protein, post-translational modification, Alzheimer's disease, amyloid precursor protein, acetylation, ubiquitination, lysine methylation, O-GlcNAcylation, lysine residues, neurodegeneration
MeSH terms: Acetylation, Animals, Methylation, Mice, Inbred C57BL, Mice, Transgenic, Protein Processing, Post-Translational, Mass Spectrometry, Amyloid beta-Protein Precursor, tau Proteins, Mice, Ubiquitination

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Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice

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