Abnormal tau phosphorylation in the thorny excrescences of CA3 hippocampal neurons in patients with Alzheimer’s disease
Open accessAbstract
A key symptom in the early stages of Alzheimer's disease (AD) is the loss of declarative memory. The anatomical substrate that supports this kind of memory involves the neural circuits of the medial temporal lobe, and in particular, of the hippocampal formation and adjacent cortex. A main feature of AD is the abnormal phosphorylation of the tau protein and the presence of tangles. The sequence of cellular changes related to tau phosphorylation and tangle formation has been studied with an antibody that binds to diffuse phosphotau (AT8). Moreover, another tau antibody (PHF-1) has been used to follow the pathway of neurofibrillary (tau aggregation) degeneration in AD. We have used a variety of quantitative immunocytochemical techniques and confocal microscopy to visualize and characterize neurons labeled with AT8 and PHF-1 antibodies. We present here the rather unexpected discovery that in AD, there is conspicuous abnormal phosphorylation of the tau protein in a selective subset of dendritic spines. We identified these spines as the typical thorny excrescences of hippocampal CA3 neurons in a pre-tangle state. Since thorny excrescences represent a major synaptic target of granule cell axons (mossy fibers), such aberrant phosphorylation may play an essential role in the memory impairment typical of AD patients.
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PHF-tauAT8 mostly labels the initial stages of a neurofibrillar pathology, while PHF-tauPHF-1 recognizes the later stages.
“Indeed, the vast majority of PHF-tauPHF-1-ir neurons had a large amount of aggregated tau, consistent with the hypothesis that PHF-tauAT8 mostly labels the initial stages of a neurofibrillar pathology, while PHF-tauPHF-1 recognizes the later stages (Blazquez-Llorca et al., 2011).”
From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Blazquez-Llorca et al., 2011
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Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
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“In addition, we used double labeling immunocytochemistry and confocal microscopy to examine whether PHF-tau positive thorny excrescences are innervated by glutamatergic terminals.”
MethodSpires, T. L., Meyer-Luehmann, M., Stern, E. A., McLean, P. J., Skoch, J., Nguyen, P. T., Bacskai, B. J., & Hyman, B. T. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1879-05.2005 · Cited by 550 · cited 1× · see citing works
“Since amyloid plaques induce morphological changes in dendritic spines [23–26], we wondered if the presence of these giant thorny excrescences could reflect the fact that amyloid plaques were in contact or adjacent to these PHF-tauAT8-ir neurons.”
BackgroundArendt, T., Stieler, J., Strijkstra, A. M., Hut, R. A., Rüdiger, J., Van der Zee, E. A., Harkany, T., Holzer, M., & Härtig, W. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-18-06972.2003 · Cited by 357 · see citing works
Popov, V. I., & Bocharova, L. S. (1992) · Neuroscience · doi:10.1016/0306-4522(92)90337-2 · Cited by 203 · see citing works
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Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · see citing works
Analyzing dendritic spine pathology in Alzheimer’s disease: Problems and opportunities
Dorostkar, M. M., Zou, C., Blazquez-Llorca, L., & Herms, J. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1449-5 · Cited by 235 · see citing works
Merino-Serrais, P., Benavides-Piccione, R., Blazquez-Llorca, L., Kastanauskaite, A., Rábano, A., Avila, J., & DeFelipe, J. (2013) · Brain · doi:10.1093/brain/awt088 · Cited by 134 · see citing works
Self-citationCrowe, S. E., & Ellis‐Davies, G. C. R. (2013) · Journal of Comparative Neurology · doi:10.1002/cne.23306 · Cited by 15 · see citing works
- Authors
- Blazquez-Llorca, L., Garcia-Marin, V., Merino-Serrais, P., Ávila, J., & DeFelipe, J.
- Affiliations
- Laboratorio de Circuitos Corticales (CTB), Universidad Politécnica de Madrid, Campus Montegancedo S/N, Pozuelo de Alarcón, Spain
- Center for Neural Science, New York University, New York, NY, USA
- Consejo Superior de Investigaciones Científicas (ES)
- Instituto Cajal (ES)
- Corresponding author
- DeFelipe, Javier
- Venue
- Journal of Alzheimer’s Disease
- Publisher
- SAGE Publications
- Published
- 2011-10-04
- Volume
- 26
- Issue
- 4
- Pages
- 683-698
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2098666649
- Cited by
- 44
- References
- 5
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 6 · 2014: 3 · 2013: 7 · 2012: 3
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CB06/05/0066)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, tau phosphorylation
- MeSH terms
- Adult, Aged, Aged, 80 and over, Alzheimer Disease, DNA-Binding Proteins, Female, Humans, Immunohistochemistry, Male, Middle Aged, Neurons, Phosphorylation, Transcription Factors, Amyloid beta-Peptides, Neurofibrillary Tangles, tau Proteins, Microscopy, Confocal, Young Adult, CA3 Region, Hippocampal, Plaque, Amyloid, Polycomb-Group Proteins
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