Microtubule-associated protein tau is essential for long-term depression in the hippocampus
Open accessAbstract
The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimer's disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro , an effect that was replicated by RNAi knockdown of tau in vitro . We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.
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Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.
“Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [41]
The Discussion (page unavailable) links dysregulation of tau’s normal function to neuronal pathology and describes hyperphosphorylation, neurofibrillary tangles, and missorting into somatodendrites. The Introduction (page unavailable) also associates tau accumulation with synapse and neuron loss. The paper does not establish gain of toxic function as a distinct mechanism, so it does not support the full four-part claim. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe literature has established a role for tau in regulating glutamatergic synaptic function, where it interacts with Fyn, NMDARs, PSD-95, and SynGAP1.
“The literature has established a role for tau in regulating glutamatergic synaptic function, where it interacts with Fyn, NMDARs, PSD-95, and SynGAP1 [41, 77, 105].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [41]
The Discussion reports that tau is required for hippocampal long-term depression, supporting a role in synaptic function. The Results place tau in a PSD-95-rich fraction, and the Discussion says NMDAR activation can affect its localization, but neither establishes direct interaction with PSD-95 or NMDARs. The searched passages do not support interactions with Fyn or SynGAP1. Page numbers were not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPost-synaptic Tau is crucial for LTD.
“Post-synaptic Tau has been demonstrated to be crucial for LTD [73].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [73]
The Results show that tau knockdown in CA1 neurons blocks LTD, and the section ‘Tau is found in the postsynaptic compartment’ detects tau in dendritic spines. But that section says postsynaptic tau ‘could, in principle, function directly in LTD’; it does not demonstrate that the postsynaptic fraction specifically is crucial. (LLM, conf=0.84)
Experimental — accuracy not yet measuredDendritic tau may regulate synaptic plasticity; synaptic activity can recruit tau to postsynaptic densities, and tau deletion in various mouse models shows deficits in LTP or LTD.
“Dendritic tau may also play a role in regulating synaptic plasticity, as synaptic activity can recruit tau to the postsynaptic densities, where tau deletion in various mouse models show deficits either in LTP or LTD [129, 131, 132].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [132]
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References 41 · Cited by 307
- Authors
- Kimura, T., Whitcomb, D. J., Jo, J., Regan, P., Piers, T., Heo, S., Brown, C., Hashikawa, T., Murayama, M., Seok, H., Sotiropoulos, I., Kim, E., Collingridge, G. L., Takashima, A., & Cho, K.
- Affiliations
- Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology (JP)
- University of Bristol (GB)
- Chonnam National University Hospital (KR)
- RIKEN Center for Brain Science (JP)
- Korea Advanced Institute of Science and Technology (KR)
- Seoul National University (KR)
- Corresponding author
- Takashima, Akihiko
- Cho, Kwangwook
- ORCID
- Venue
- Philosophical Transactions of the Royal Society B: Biological Sciences
- Publisher
- The Royal Society
- Published
- 2014-01-05
- Volume
- 369
- Issue
- 1633
- Pages
- 20130144
- ISSN
- 0962-8436 (ISSN-L)
- 1471-2970
- PMC
- PMC3843876
- OpenAlex
- W2096361230
- Cited by
- 307
- References
- 41
- Citations by year
- 2026: 18 · 2025: 22 · 2024: 18 · 2023: 20 · 2022: 31 · 2021: 35 · 2020: 34 · 2019: 20 · 2018: 34 · 2017: 28 · 2016: 15 · 2015: 19 · 2014: 10 · 2013: 3
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Philosophical Transactions of the Royal Society B Biological Sciences (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Wellcome Trust (089703)
- Royal Society
- Great Britain Sasakawa Foundation
- National Center for Geriatrics and Gerontology
- Universidade do Minho
- Medical Research Council (MR/K023098/1, MC_G1000734)
- Biotechnology and Biological Sciences Research Council (BB/G003963/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- tau protein, long-term depression, hippocampus, synaptic plasticity, glycogen synthase kinase-3, tau phosphorylation, tau knockout mice, RNAi knockdown, Alzheimer's disease, tauopathy, neurofibrillary tangles
- MeSH terms
- Animals, Hippocampus, Immunohistochemistry, Male, Mice, Inbred C57BL, Microscopy, Electron, Phosphorylation, Subcellular Fractions, Synapses, Blotting, Western, tau Proteins, Rats, Wistar, Mice, Knockout, Tauopathies, RNA Interference, Long-Term Synaptic Depression, Glycogen Synthase Kinase 3, Microdissection, Mice, Rats
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