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Cited by 134Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

The DOI matches its Crossref record; 90 of the 91 references it cites were found in a registry or an index; 25 of the 62 sources its claims cite were checked for support.

The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease

Open access
Merino-Serrais, Paula, Benavides-Piccione, Ruth, Blazquez-Llorca, Lidia, Kastanauskaite, Asta, Rábano, Alberto, Avila, Jesús, DeFelipe, Javier·2013·Brain
DOI 10.1093/brain/awt088PMC PMC3673457
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Abstract

The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer's disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer's disease is likely to depend on the relative number of neurons that have well developed tangles.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In human Alzheimer’s disease tissue, diffuse phospho-tau in a putative pre-tangle state did not alter dendritic spine or dendrite morphology, whereas tau aggregates forming neurofibrillary tangles were associated with progressive spine loss, smaller/shorter spines, and dendrite atrophy. The authors conclude that phospho-tau presence alone does not necessarily cause severe irreversible damage; cognitive impairment may depend on the relative number of neurons with well-developed tangles.

Key findings

  • Across 42 Lucifer yellow-injected neurons and 19,569 dendritic spines, neurons with Pattern I diffuse phospho-tau showed no significant differences from PHF-tau− neurons in dendrite diameter, spine density, spine length, or spine volume in parahippocampal cortex Patient P9.
  • In CA1 Pattern IIa neurons, changes varied by patient: Patient P9 had 22% smaller average dendrite diameter and 14% shorter average spine length; Patients P13 and P14 showed lower dendritic spine density in medial/distal dendrites; all three patients showed a higher frequency of small spines in PHF-tau+ neurons.
  • Pattern IIb neurons with well-developed tangles had reduced dendritic arbors, remarkably thin dendrites, and few or virtually no dendritic spines.
  • Distal dendritic segments with fibrillar PHF-tauAT8 had significantly lower spine density than adjacent pre-terminal segments lacking PHF-tauAT8, suggesting a local toxic effect.

Methods

  • Human autopsy brain tissue from n = 5 patients; quantitative morphometry focused on Patients P9, P13, and P14, with neurons in layer III of parahippocampal cortex and CA1 pyramidal layer.
  • Individual pyramidal cells were injected intracellularly with Lucifer yellow in fixed tissue, then sections were immunostained for anti-Lucifer yellow and tau antibodies AT8 (Ser202/Thr205) and PHF-1 (Ser396/404); spines were scanned by confocal microscopy and reconstructed in three dimensions.
  • Measured dendrite diameter, dendritic spine density, spine length, and spine volume; statistics used Mann-Whitney tests, Kolmogorov-Smirnov tests for frequency distributions, and two-way ANOVA with Bonferroni post hoc comparisons for distance-from-soma analyses.

Limitations

  • The paper states that relatively few cells can be injected, pyramidal cell structure differs by cortical region, human pathological tissue has high interindividual variability, the proportion of cells with neurofibrillar pathology is unpredictable before injection, and both AT8 and PHF-1 antibodies were mouse-produced so double labeling could reflect cross-reactivity.
  • The paper notes uncertainty about whether Pattern I represents a pre-tangle stage preceding Pattern II or an independent subpopulation, and it cannot determine whether findings generalize to neurons with other phosphorylated tau epitopes.
  • Evident from the text: the quantitative sample is small and drawn from only three patients, the design is cross-sectional autopsy tissue, and the study cannot establish causality or track progression within individual neurons over time.

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Integrity signals

Registry

Crossref · 10.1093/brain/awt088

Cites

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Figures

Figure 1 Localization of intracellular injections and histopathology. Low-power photomicrographs of Nissl (A), amyloid-β/Nissl (B), PHF-tauAT8 (C) and PHF-tauPHF-1 (D) stained sections from Patient P9. The black dots in (A) show the approximate location of the injected neurons in layer III of the parahippocampal cortex (PHC) and CA1 region. These sections are shown at higher magnification in Supplementary Figs 1 and 2. Scale bars: A–D = 1600 µm. GD = dentate gyrus.
Figure 1 Localization of intracellular injections and histopathology. Low-power photomicrographs of Nissl (A), amyloid-β/Nissl (B), PHF-tauAT8 (C) and PHF-tauPHF-1 (D) stained sections from Patient P9. The black dots in (A) show the approximate location of the injected neurons in layer III of the parahippocampal cortex (PHC) and CA1 region. These sections are shown at higher magnification in Supplementary Figs 1 and 2. Scale bars: A–D = 1600 µm. GD = dentate gyrus.CC BY-NC · PubMed Central
Figure 2 Neuronal density. Graph showing the neuronal density in the parahippocampal cortex and CA1 regions of Patients P9, P13 and P14. Blue columns: total neuron density; red columns: PHF-tauAT8-ir neuron density; black columns: PHF-tauPHF-1-ir neuron density. The percentages indicated at the top of the red and black columns represent the percentage of phospho-tau neurons with respect to the total neuron density in each region.
Figure 2 Neuronal density. Graph showing the neuronal density in the parahippocampal cortex and CA1 regions of Patients P9, P13 and P14. Blue columns: total neuron density; red columns: PHF-tauAT8-ir neuron density; black columns: PHF-tauPHF-1-ir neuron density. The percentages indicated at the top of the red and black columns represent the percentage of phospho-tau neurons with respect to the total neuron density in each region.CC BY-NC · PubMed Central
Figure 3 Patterns of PHF-tau immunostaining. Confocal microscopy images showing neurons in parahippocampal cortex (A–C) and CA1 (D–I) double-stained with PHF-tauAT8 (red) and thioflavin S (green) (D–I) to illustrate Pattern I (neuron indicated with an arrow), Pattern IIa and Pattern IIb of immunostaining. Scale bars: A–I = 10 µm.
Figure 3 Patterns of PHF-tau immunostaining. Confocal microscopy images showing neurons in parahippocampal cortex (A–C) and CA1 (D–I) double-stained with PHF-tauAT8 (red) and thioflavin S (green) (D–I) to illustrate Pattern I (neuron indicated with an arrow), Pattern IIa and Pattern IIb of immunostaining. Scale bars: A–I = 10 µm.CC BY-NC · PubMed Central
Figure 4 PHF-tau− neurons and neurons with Pattern I PHF-tauAT8 staining. Neurons and dendrites in the parahippocampal cortex of Patient P9 injected with Lucifer yellow whose soma is free of PHF-tauAT8-ir (; A–F) or that contains PHF-tauAT8 in the putative pre-tangle state (Pattern I; G–L). Stacks of 26 (A and B) and 28 (G and H) images, respectively, obtained after combining the channels acquired separately for DAPI (blue), Lucifer yellow (green) and PHF-tauAT8 immunostaining (red). (C–L) Stacks of 26–32 confocal optical sections from basal dendrites of (C–F) and immunostained (; I–L) Lucifer yellow-injected pyramidal neurons. The cell bodies of the neurons in B and H are shown at higher magnification in Supplementary Fig. 3A–F and G–L, respectively. These and Lucifer yellow-injected neurons were recovered and reprocessed immunocytochemically using anti-PHF-tauPHF-1. The neuron was non-immunostained for PHF-tauPHF-1 (PHF-tau−). Scale bars: A, B, G and H = 13 µm; C–F and I–L = 2 µm.
Figure 4 PHF-tau− neurons and neurons with Pattern I PHF-tauAT8 staining. Neurons and dendrites in the parahippocampal cortex of Patient P9 injected with Lucifer yellow whose soma is free of PHF-tauAT8-ir (; A–F) or that contains PHF-tauAT8 in the putative pre-tangle state (Pattern I; G–L). Stacks of 26 (A and B) and 28 (G and H) images, respectively, obtained after combining the channels acquired separately for DAPI (blue), Lucifer yellow (green) and PHF-tauAT8 immunostaining (red). (C–L) Stacks of 26–32 confocal optical sections from basal dendrites of (C–F) and immunostained (; I–L) Lucifer yellow-injected pyramidal neurons. The cell bodies of the neurons in B and H are shown at higher magnification in Supplementary Fig. 3A–F and G–L, respectively. These and Lucifer yellow-injected neurons were recovered and reprocessed immunocytochemically using anti-PHF-tauPHF-1. The neuron was non-immunostained for PHF-tauPHF-1 (PHF-tau−). Scale bars: A, B, G and H = 13 µm; C–F and I–L = 2 µm.CC BY-NC · PubMed Central
Figure 5 PHF-tau− and neurons with Pattern IIa PHF-tauAT8 staining. Neurons and dendrites in the CA1 of Patients P14 (A–J) and P13 (K–O), injected with Lucifer yellow, and with a soma free of PHF-tauAT8 (; A–E) or with PHF-tauAT8–ir tangles (Pattern IIa; F–O). (A–B, F–G and K–L) Stacks of 18 and 35 images, respectively, obtained after combining the channels acquired separately for Lucifer yellow (green) and PHF-tauAT8 (red). (C–D, H–J and M–O) Stacks of 26–58 optical confocal sections of the basal dendrites of (A and B) and immunostained (; F–G, K–L) Lucifer yellow-injected pyramidal neurons. These and Lucifer yellow-injected neurons were recovered and reprocessed immunocytochemically using anti-PHF-tauPHF-1. The neuron was non-immunostained for PHF-tauPHF-1 (PHF-tau−), whereas the neurons were also PHF-tauPHF-1 (Supplementary Fig. 5). Scale bars: A, F and K = 10 µm; C–E, H–J and M–O = 3 µm.
Figure 5 PHF-tau− and neurons with Pattern IIa PHF-tauAT8 staining. Neurons and dendrites in the CA1 of Patients P14 (A–J) and P13 (K–O), injected with Lucifer yellow, and with a soma free of PHF-tauAT8 (; A–E) or with PHF-tauAT8–ir tangles (Pattern IIa; F–O). (A–B, F–G and K–L) Stacks of 18 and 35 images, respectively, obtained after combining the channels acquired separately for Lucifer yellow (green) and PHF-tauAT8 (red). (C–D, H–J and M–O) Stacks of 26–58 optical confocal sections of the basal dendrites of (A and B) and immunostained (; F–G, K–L) Lucifer yellow-injected pyramidal neurons. These and Lucifer yellow-injected neurons were recovered and reprocessed immunocytochemically using anti-PHF-tauPHF-1. The neuron was non-immunostained for PHF-tauPHF-1 (PHF-tau−), whereas the neurons were also PHF-tauPHF-1 (Supplementary Fig. 5). Scale bars: A, F and K = 10 µm; C–E, H–J and M–O = 3 µm.CC BY-NC · PubMed Central
Figure 6 Neurons with Pattern IIb of PHF-tau immunostaining. Alterations of dendrites and dendritic spines in Lucifer yellow injected neurons with Pattern IIb PHF-tauAT8-ir from layer III of the parahippocampal cortex in Patient P9 (A–C) and Pattern IIb PHF-tauPHF-1-ir in the CA1 of Patient P12 (D–L). (A) Stack of 27 confocal optical sections obtained after combining the channels acquired separately for DAPI (blue), Lucifer yellow (green) and PHF-tauAT8-ir (red), showing the cell body and proximal dendrites of the intracellular labelled neuron with Pattern IIb PHF-tauAT8–ir. (B and C) Higher magnification of A, showing the dendrites indicated as ‘b’ and ‘c’, respectively. Note the low density of dendritic spines in dendrite ‘b’ compared with dendrite ‘c’, and in the latter dendrite compared with the dendrites in Figs 4 and 5. Also, the dendritic spines are notably smaller. (D–E) Stacks of 27 confocal optical sections showing the cell body and proximal dendrites of the intracellular labelled neuron (D) with Pattern IIb PHF-tauPHF-1–ir (E). (F) Image obtained by combining D and E. (G) Higher magnification of D. (H and I) Stacks of 38–55 confocal optical sections from a collateral apical dendrite (arrow in G) of the Lucifer yellow-injected pyramidal neuron, showing different segments of the same dendrite (H, proximal; I, distant). (J) Stack of 26 confocal optical sections from the collateral apical dendrite of an intracellular labelled neuron that was adjacent to the Lucifer yellow-injected neuron shown in D, and that was not PHF-tauPHF-1–ir. Note the lack of dendritic spines and the thin diameter of the dendrites of the PHF-tauPHF-1-ir neuron (H and I) compared with the dendrite of the PHF-tau− neuron (J). Scale bars: A = 10 µm; B and C = 3.5 µm; D–F = 20 µm; G = 9 µm; H–J = 4.5 µm.
Figure 6 Neurons with Pattern IIb of PHF-tau immunostaining. Alterations of dendrites and dendritic spines in Lucifer yellow injected neurons with Pattern IIb PHF-tauAT8-ir from layer III of the parahippocampal cortex in Patient P9 (A–C) and Pattern IIb PHF-tauPHF-1-ir in the CA1 of Patient P12 (D–L). (A) Stack of 27 confocal optical sections obtained after combining the channels acquired separately for DAPI (blue), Lucifer yellow (green) and PHF-tauAT8-ir (red), showing the cell body and proximal dendrites of the intracellular labelled neuron with Pattern IIb PHF-tauAT8–ir. (B and C) Higher magnification of A, showing the dendrites indicated as ‘b’ and ‘c’, respectively. Note the low density of dendritic spines in dendrite ‘b’ compared with dendrite ‘c’, and in the latter dendrite compared with the dendrites in Figs 4 and 5. Also, the dendritic spines are notably smaller. (D–E) Stacks of 27 confocal optical sections showing the cell body and proximal dendrites of the intracellular labelled neuron (D) with Pattern IIb PHF-tauPHF-1–ir (E). (F) Image obtained by combining D and E. (G) Higher magnification of D. (H and I) Stacks of 38–55 confocal optical sections from a collateral apical dendrite (arrow in G) of the Lucifer yellow-injected pyramidal neuron, showing different segments of the same dendrite (H, proximal; I, distant). (J) Stack of 26 confocal optical sections from the collateral apical dendrite of an intracellular labelled neuron that was adjacent to the Lucifer yellow-injected neuron shown in D, and that was not PHF-tauPHF-1–ir. Note the lack of dendritic spines and the thin diameter of the dendrites of the PHF-tauPHF-1-ir neuron (H and I) compared with the dendrite of the PHF-tau− neuron (J). Scale bars: A = 10 µm; B and C = 3.5 µm; D–F = 20 µm; G = 9 µm; H–J = 4.5 µm.CC BY-NC · PubMed Central
Figure 7 Dendritic spine density. Comparative morphometric analysis of dendrites from Lucifer yellow-injected PHF-tau+ pyramidal neurons and dendrites from Lucifer yellow-injected PHF-tau− neurons in the CA1 of Patient P9 (A and B), Patient P13 (C and D) and Patient P14 (E and F). (A, C and E) Dendritic spine density (dendritic spines/µm) in function of the distance from soma. (B, D and F) Average dendritic spine density per dendrite. *P < 0.05; **P < 0.01.
Figure 7 Dendritic spine density. Comparative morphometric analysis of dendrites from Lucifer yellow-injected PHF-tau+ pyramidal neurons and dendrites from Lucifer yellow-injected PHF-tau− neurons in the CA1 of Patient P9 (A and B), Patient P13 (C and D) and Patient P14 (E and F). (A, C and E) Dendritic spine density (dendritic spines/µm) in function of the distance from soma. (B, D and F) Average dendritic spine density per dendrite. *P < 0.05; **P < 0.01.CC BY-NC · PubMed Central
Figure 8 Morphometric analysis. Comparative morphometric analysis of dendritic spine length (A–I) and dendritic spine volume (J–R) for Lucifer yellow-injected PHF-tau+ pyramidal neurons and Lucifer yellow-injected PHF-tau− neurons from the CA1 of each patient in function of the distance from soma (A, D, G, J, M and P). The average per dendrite (B, E, H, K, N and Q) and the frequency distribution (C, F, I, L, O and R) are shown: *P < 0.05; **P < 0.01; ***P < 0.001.
Figure 8 Morphometric analysis. Comparative morphometric analysis of dendritic spine length (A–I) and dendritic spine volume (J–R) for Lucifer yellow-injected PHF-tau+ pyramidal neurons and Lucifer yellow-injected PHF-tau− neurons from the CA1 of each patient in function of the distance from soma (A, D, G, J, M and P). The average per dendrite (B, E, H, K, N and Q) and the frequency distribution (C, F, I, L, O and R) are shown: *P < 0.05; **P < 0.01; ***P < 0.001.CC BY-NC · PubMed Central
Figure 9 Scheme representing the changes to dendrites of Lucifer yellow-injected neurons that showed different patterns of PHF-tau immunostaining. For simplicity, dendritic spines were represented as two types: small and large. Red = phospho-tau.
Figure 9 Scheme representing the changes to dendrites of Lucifer yellow-injected neurons that showed different patterns of PHF-tau immunostaining. For simplicity, dendritic spines were represented as two types: small and large. Red = phospho-tau.CC BY-NC · PubMed Central

Verification

Claims the paper makes

29 Own result · 23 Own interpretation · 13 Partly supported · 8 Sources not found · 7 No full text of the sources · 5 Own method · 3 Supported · 3 Supported so far · 2 Not checked yet · accuracy not yet measured

Show all 47 claims

  • Probably not a substantial claim. 22
  • It may state two separate claims as one. 30
46 of 46

  • The paper relies on this without support.

    Loss of synapses leads to cognitive decline in Alzheimer’s disease.

    “the presence of PHF-tau is likely to be involved in the changes to dendritic spines and the loss of synapses that leads to cognitive decline in Alzheimer’s disease.”

  • The paper relies on this without support.

    Lower density of neurons in CA3 indicates more advanced CA3 pathology.

    “the density of neurons in the CA3 was lower in these latter patients than in Patient P9 (38% and 42% fewer neurons, respectively), suggesting that the CA3 pathology was more advanced in these patients than in Patient P9”

  • The authors state this as an assumption.

    One spine corresponds to one excitatory synapse.

    “Assuming the hypothesis that one spine corresponds to one excitatory synapses (Arellano et al., 2007b)”

  • The authors state this as an assumption.

    The majority of dendritic spines establish synapses.

    “Assuming that the majority of the dendritic spines establish synapses (Arellano et al., 2007b)”

  • The authors state this as an assumption.

    Neuronal degeneration and atrophy is progressive.

    “if we assume the widely accepted hypothesis that neuronal degeneration and atrophy is progressive”
5 of 5

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3 of 3

Citations

Cites

Show all 91 references

Research works printed but not linked: 1

  1. Buhl, 1990, Intracellular injection of neurons in fixed brain tissue combined with other neuroanatomical techniques at the light- and electron- microscopic level, 273

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Metadata

Authors
Merino-Serrais, P., Benavides-Piccione, R., Blazquez-Llorca, L., Kastanauskaite, A., Rábano, A., Avila, J., & DeFelipe, J.
Affiliations
  • Consejo Superior de Investigaciones Científicas (ES)
  • Fundacion Centro De Investigacion De Enfermedades Neurologicas (ES)
Corresponding author
DeFelipe, Javier
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2013-05-28
Volume
136
Issue
6
Pages
1913-1928
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awt088
PMC
PMC3673457
OpenAlex
W2121418448
Cited by
134
References
91
Citations by year
2026: 3 · 2025: 9 · 2024: 6 · 2023: 15 · 2022: 10 · 2021: 13 · 2020: 17 · 2019: 8 · 2018: 7 · 2017: 16 · 2016: 8 · 2015: 10 · 2014: 10 · 2013: 2
FWCI
6.96
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Brain (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc)
Funders
Ministerio de Economía y Competitividad
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, tau phosphorylation, phosphorylated tau, dendritic spines, pyramidal neurons, neurofibrillary tangles, parahippocampal cortex, CA1, postsynaptic structures, cognitive impairment
MeSH terms
Alzheimer Disease, Cell Count, Cerebral Cortex, Humans, Phosphorylation, tau Proteins, Pyramidal Cells, Dendritic Spines

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