Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration
Open accessAbstract
The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines.
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Tau is partially re-localized to the post-synaptic domain where it is thought to promote Aβ toxicity in pathological conditions by modifying NMDAR activation.
“In this context, Tau is partially re-localized to the post-synaptic domain where it is thought to promote Aβ toxicity in pathological conditions by modifying NMDAR activation [53].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [53]
The Discussion reports that pathological tau becomes enriched in the postsynaptic density and mislocalizes to dendritic spines. It also reports impaired NMDAR trafficking or anchoring, but does not establish that this promotes Aβ toxicity by modifying NMDAR activation; it notes that a cited study found no change in NMDAR-mediated currents. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMany disease-associated phosphorylated residues cluster within the proline-rich region of the N-terminal projection domain and the C-terminal region adjacent to the microtubule-binding repeats.
“Many disease-associated phosphorylated residues cluster within the proline-rich region of the N-terminal projection domain and the C-terminal region adjacent to the microtubule-binding repeats (Fulga et al., 2007; Steinhilb et al., 2007; Hoover et al., 2010; Wesseling et al., 2020).”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Hoover et al., 2010
The Results section (‘Role of phosphorylation in htau mislocalization’; page unavailable) describes tau’s projection and microtubule-binding domains, while the Discussion identifies 14 disease-relevant serine and threonine phosphorylation sites. Neither passage says that these sites cluster in the two specific regions named in the claim. (LLM, conf=0.82)
Experimental — accuracy not yet measuredThe 14 disease-associated mutations used here to mimic hyperphosphorylation are located within these regions.
“The 14 disease-associated mutations used here to mimic hyperphosphorylation are located within these regions”
From Tau hyperphosphorylation impairs cooperative binding to microtubules and perturbs organelle trafficking in neurons (2026) · cites this paper as Hoover et al., 2010
The Results section describes changing 14 serine/threonine residues to glutamate to mimic phosphorylation, and Experimental Procedures lists their positions. The copy describes tau’s structural regions but does not explicitly establish that all 14 sites lie within the unspecified “these regions,” so the location claim cannot be fully checked. (LLM, conf=0.78)
Experimental — accuracy not yet measuredThe route of synaptic damage may be multifocal, with impaired axonal transport from tau dysfunction complemented by hyperphosphorylated tau in dendritic spines and impaired synaptic transmission.
“The route of synaptic damage may be multifocal, as impaired axonal transport resulting from tau dysfunction may be complemented by the arrival of hyperphosphorylated tau in dendritic spines and concomitant impaired synaptic transmission [98].”
From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [98]
Phosphorylation can alter tau subcellular localization to dendritic spines or alter its affinity for the plasma membrane, thereby causing alterations in synaptic function.
“Apart from its effects on microtubule binding, phosphorylation can alter tau subcellular localization to dendritic spines (127) or can alter its affinity for the plasma membrane (128), thereby causing alterations in synaptic function (127,129).”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [127]
Cognitive impairment in spatial reference memory and synaptic dysfunction in hippocampal CA1 pyramidal neurons begin to manifest at 4.5 months of age in rTg4510 mice.
“Cognitive impairment in spatial reference memory and synaptic dysfunction in hippocampal CA1 pyramidal neurons begin to manifest at 4.5 months of age (37).”
rTg4510 neurons have fewer NMDARs on their dendritic spines due to the mislocalization of tau protein from axons to dendritic spines.
“A recent study by Hoover et al. (37) found that rTg4510 neurons have fewer NMDARs on their dendritic spines due to the mislocalization of tau protein from axons to dendritic spines.”
Cultured hippocampal neurons expressing P301L tau had deficits in synaptic transmission due to loss of surface AMPA receptors, but no gross reductions in spine density.
“Hoover et al. (2010) revealed that cultured hippocampal neurons expressing P301L tau had deficits in synaptic transmission due to loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, but no gross reductions in spine density.”
From Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice (2021) · cites this paper as Hoover et al., 2010
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 Hoover et al., 2010
Mutant tau hyperphosphomimetic Ser/Thr isoforms promote tau distribution to dendritic spines and impair synaptic function.
“While phosphorylation at S396 plays a key role in the induction and maintenance of hippocampal LTD [142], mutant tau hyperphosphomimetic Ser/Thr isoforms promotes tau distribution to dendritic spines and impairs synaptic function [143].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [143]
Perineuronal net loss in AD may contribute to synaptic loss.
“synaptic loss (Scheibel and Tomiyasu, 1978; Ruiter and Uyling, 1987; Hoover et al., 2010)”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Hoover et al., 2010
Hyperphosphorylated tau is redirected from the axonal to the somatodendritic compartment, where it can impair synaptic function by inhibiting glutamate receptor trafficking or synaptic anchoring.
“Hyperphosphorylated tau is also redirected from the axonal compartment to the somatodendritic compartment where it can impair synaptic function by inhibiting glutamate receptor trafficking or synaptic anchoring”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Hoover et al., 2010
Dissociation from microtubules and formation of neurofibrillary tangles cause impairment of axonal transport, cytoskeletal and mitochondrial dysfunction, oxidative stress, and synaptic loss, and increase cytosolic tau further promoting its aggregation and fibrillization.
“The dissociation from microtubules and the formation of NFTs in turn cause the impairment of the axonal transport, cytoskeletal and mitochondrial dysfunction, oxidative stress, and synaptic loss (Hoover et al., 2010) and, moreover, increase the cytosolic content of tau further promoting its aggregation and fibrillization.”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Hoover et al., 2010
Neurons exhibit dendritic spine loss, synaptic dysfunction, and eventual degeneration in response to Aβ and tau pathology.
“Neurons exhibit dendritic spine loss, synaptic dysfunction, and eventual degeneration in response to Aβ and tau pathology (Hoover et al., 2010; Shankar et al., 2007).”
From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Hoover et al., 2010
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- Authors
- Hoover, B. R., Reed, M. N., Su, J., Penrod, R. D., Kotilinek, L. A., Grant, M. K., Pitstick, R., Carlson, G. A., Lanier, L. M., Yuan, L.-L., Ashe, K. H., & Liao, D.
- Affiliations
- University of Minnesota (US)
- McLaughlin Research Institute (US)
- Corresponding author
- Ashe, Karen H.
- Liao, Dezhi
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2010-12
- Volume
- 68
- Issue
- 6
- Pages
- 1067-1081
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3026458
- OpenAlex
- W1968553823
- Cited by
- 1,118
- References
- 61
- Citations by year
- 2026: 61 · 2025: 77 · 2024: 87 · 2023: 70 · 2022: 88 · 2021: 119 · 2020: 108 · 2019: 79 · 2018: 96 · 2017: 51 · 2016: 61 · 2015: 46 · 2014: 47 · 2013: 48 · 2012: 45
- FWCI
- 27.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG026252)
- National Institute on Drug Abuse (K02DA025048, T32DA022616, R01DA020582, T32DA007234)
- National Cancer Institute (P30CA-77598, P30CA077598)
- National Institute of Neurological Disorders and Stroke (R01NS063214, R01NS049129, R01NS049178)
- 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 protein, hyperphosphorylation, dendritic spines, synaptic dysfunction, glutamate receptor trafficking, Alzheimer's disease, neurodegeneration, presynaptic dysfunction
- MeSH terms
- Animals, Cells, Cultured, Memory Disorders, Mice, Transgenic, Nerve Degeneration, Phosphorylation, Synapses, tau Proteins, Dendritic Spines, Mice, Rats
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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