Tau phosphorylation and tau mislocalization mediate soluble Aβ oligomer‐induced AMPA glutamate receptor signaling deficits
Open accessAbstract
In our previous studies, phosphorylation‐dependent tau mislocalization to dendritic spines resulted in early cognitive and synaptic deficits. It is well known that amyloid beta (Aβ) oligomers cause synaptic dysfunction by inducing calcineurin‐dependent AMPA receptor ( AMPAR ) internalization. However, it is unknown whether Aβ‐induced synaptic deficits depend upon tau phosphorylation. It is also unknown whether changes in tau can cause calcineurin‐dependent loss of AMPAR s in synapses. Here, we show that tau mislocalizes to dendritic spines in cultured hippocampal neurons from APP Swe Alzheimer's disease ( AD )‐transgenic mice and in cultured rat hippocampal neurons treated with soluble Aβ oligomers. Interestingly, Aβ treatment also impairs synaptic function by decreasing the amplitude of miniature excitatory postsynaptic currents (m EPSC s). The above tau mislocalization and Aβ‐induced synaptic impairment are both diminished by the expression of AP tau, indicating that these events require tau phosphorylation. The phosphatase activity of calcineurin is important for AMPAR internalization via dephosphorylation of GluA1 residue S845. The effects of Aβ oligomers on m EPSC s are blocked by the calcineurin inhibitor FK506. Aβ‐induced loss of AMPAR s is diminished in neurons from knock‐in mice expressing S845A mutant GluA1 AMPA glutamate receptor subunits. This finding suggests that changes in phosphorylation state at S845 are involved in this pathogenic cascade. Furthermore, FK506 rescues deficits in surface AMPAR clustering on dendritic spines in neurons cultured from transgenic mice expressing P301L tau proteins. Together, our results support the role of tau and calcineurin as two intermediate signaling molecules between Aβ initiation and eventual synaptic dysfunction early in AD pathogenesis.
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Our findings in the hippocampus support in vitro studies showing that hyperphosphorylated tau does not induce spine loss in primary hippocampal neuron cultures or organotypic slices.
“Our findings in the hippocampus support in vitro studies showing that hyperphosphorylated tau does not induce spine loss in primary hippocampal neuron cultures or organotypic slices (Shahani et al., 2006, Hoover et al., 2010, Miller et al., 2014).”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Miller et al., 2014
The Results section reports that Aβ-treated primary hippocampal neurons showed tau mislocalization without a significant change in spine density over one to three days. This supports the culture finding, but the paper does not establish that hyperphosphorylated tau itself cannot induce spine loss, and it does not report that finding in organotypic slices. The Discussion notes that longer Aβ exposure may produce permanent spine loss; page numbers were not available in our copy. (LLM, conf=0.87)
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- Authors
- Miller, E. C., Teravskis, P. J., Dummer, B. W., Zhao, X., Huganir, R. L., & Liao, D.
- Affiliations
- University of Minnesota (US)
- Johns Hopkins University (US)
- Corresponding author
- Liao, Dezhi
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2014-04
- Volume
- 39
- Issue
- 7
- Pages
- 1214-1224
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- PMC
- PMC4123852
- OpenAlex
- W2142120489
- Cited by
- 131
- References
- 17
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 21 · 2023: 10 · 2022: 5 · 2021: 10 · 2020: 18 · 2019: 7 · 2018: 13 · 2017: 13 · 2016: 9 · 2015: 6 · 2014: 4
- FWCI
- 6.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Michael J. Fox Foundation for Parkinson's Research
- American Health Assistance Foundation
- National Institute on Drug Abuse (K02DA025048, R01DA020582, T32DA007234)
- National Institute of General Medical Sciences (T32GM008471, P32-GM008471)
- National Institute of Neurological Disorders and Stroke (R01NS036715)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- tau phosphorylation, soluble amyloid-beta oligomers, AMPA receptor internalization, calcineurin, dendritic spines, synaptic dysfunction, miniature excitatory postsynaptic currents, Alzheimer's disease, P301L tau, FK506, hippocampal neurons
- MeSH terms
- Animals, Cells, Cultured, Mutation, Peptide Fragments, Phosphorylation, Amyloid beta-Peptides, Tacrolimus, tau Proteins, Receptors, AMPA, Calcineurin, Excitatory Postsynaptic Potentials, Protein Transport, Dendritic Spines, Mice, Miniature Postsynaptic Potentials, Calcineurin Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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