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Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease
Open accessAbstract
Importance: Factors associated with synapse loss beyond amyloid-β plaques and neurofibrillary tangles may more closely correlate with the emergence of cognitive deficits in Alzheimer disease (AD) and be relevant for early therapeutic intervention. Objective: To investigate whether accumulation of tau oligomers in synapses is associated with excessive synapse elimination by microglia or astrocytes and with cognitive outcomes (dementia vs no dementia [hereinafter termed resilient]) of individuals with equal burdens of AD neuropathologic changes at autopsy. Design, Setting, and Participants: This cross-sectional postmortem study included 40 human brains from the Massachusetts Alzheimer Disease Research Center Brain Bank with Braak III to IV stages of tau pathology but divergent antemortem cognition (dementia vs resilient) and cognitively normal controls with negligible AD neuropathologic changes. The visual cortex, a region without tau tangle deposition at Braak III to IV stages, was assessed after expansion microscopy to analyze spatial relationships of synapses with microglia and astrocytes. Participants were matched for age, sex, and apolipoprotein E status. Evidence of Lewy bodies, TDP-43 aggregates, or other lesions different from AD neuropathology were exclusion criteria. Tissue was collected from July 1998 to November 2020, and analyses were conducted from February 1, 2022, through May 31, 2023. Main Outcomes and Measures: Amyloid-β plaques, tau neuropil thread burden, synapse density, tau oligomers in synapses, and internalization of tau oligomer–tagged synapses by microglia and astrocytes were quantitated. Analyses were performed using 1-way analysis of variance for parametric variables and the Kruskal-Wallis test for nonparametric variables; between-group differences were evaluated with Holm-Šídák tests. Results: Of 40 included participants (mean [SD] age at death, 88 [8] years; 21 [52%] male), 19 had early-stage dementia with Braak stages III to IV, 13 had resilient brains with similar Braak stages III to IV, and 8 had no dementia (Braak stages 0-II). Brains with dementia but not resilient brains had substantial loss of presynaptic (43%), postsynaptic (33%), and colocalized mature synaptic elements (38%) compared with controls and significantly higher percentages of mature synapses internalized by IBA1-positive microglia (mean [SD], 13.3% [3.9%] in dementia vs 2.6% [1.9%] in resilient vs 0.9% [0.5%] in control; P < .001) and by GFAP-positive astrocytes (mean [SD], 17.2% [10.9%] in dementia vs 3.7% [4.0%] in resilient vs 2.7% [1.8%] in control; P = .001). In brains with dementia but not in resilient brains, tau oligomers more often colocalized with synapses, and the proportions of tau oligomer–containing synapses inside microglia (mean [SD] for presynapses, mean [SD], 7.4% [1.8%] in dementia vs 5.1% [1.9%] resilient vs 3.7% [0.8%] control; P = .006; and for postsynapses 11.6% [3.6%] dementia vs 6.8% [1.3%] resilient vs 7.4% [2.5%] control; P = .001) and astrocytes (mean [SD] for presynapses, 7.0% [2.1%] dementia vs 4.3% [2.2%] resilient vs 4.0% [0.7%] control; P = .001; and for postsynapses, 7.9% [2.2%] dementia vs 5.3% [1.8%] resilient vs 3.0% [1.5%] control; P < .001) were significantly increased compared with controls. Those changes in brains with dementia occurred in the absence of tau tangle deposition in visual cortex. Conclusion and Relevance: The findings from this cross-sectional study suggest that microglia and astrocytes may excessively engulf synapses in brains of individuals with dementia and that the abnormal presence of tau oligomers in synapses may serve as signals for increased glial-mediated synapse elimination and early loss of brain function in AD.
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“Moreover, a recent study demonstrated that in addition to NFT deposition, there is a notable increase in tau oligomer-containing synapses within microglia and astrocytes during the early stages of AD but not in AsymAD cases [89].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [89]
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Yoo, K., Lee, K., Oh, J.-Y., Lee, H., Park, H., Park, Y. S., & Kim, H. K. (2019) · Molecular Brain · doi:10.1186/s13041-019-0520-x · Cited by 51
3D Analysis of the Synaptic Organization in the Entorhinal Cortex in Alzheimer’s Disease
Domínguez-Álvaro, M., Montero‐Crespo, M., Blázquez‐Llorca, L., Plaza‐Alonso, S., Cano‐Astorga, N., DeFelipe, J., & Alonso‐Nanclares, L. (2021) · eNeuro · doi:10.1523/eneuro.0504-20.2021 · Cited by 35
Distinct Neurotoxic Effects of Extracellular Tau Species in Primary Neuronal-Glial Cultures
Pampuščenko, K., Morkūnienė, R., Krasauskas, L., Smirnovas, V., Tomita, T., & Borutaitė, V. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02150-7 · Cited by 28
Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology
Romero‐Molina, C., Navarro, V., Sanchez-Varo, R. M., Jiménez, S., Fernandez-Valenzuela, J. J., Sanchez-Mico, M. V., Muñoz‐Castro, C., Gutiérrez, A., Vitórica, J., & Vizuete, M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00421 · Cited by 25
Self-citationDangerous Liaisons: Tau Interaction with Muscarinic Receptors
Wysocka, A., Pałasz, E., Steczkowska, M., & Niewiadomska, G. (2020) · Current Alzheimer Research · doi:10.2174/1567205017666200424134311 · Cited by 24
Taddei, R. N., Sanchez-Mico, M. V., Bonnar, O., Connors, T. R., Gaona, A., Denbow, D., Frosch, M. P., & Gómez‐Isla, T. (2022) · Acta Neuropathologica Communications · doi:10.1186/s40478-022-01370-3 · Cited by 23
Self-citationExpansion Revealing: Decrowding Proteins to Unmask Invisible Brain NanostructuresPreprint
Sarkar, D., Kang, J., Wassie, A. T., Schroeder, M. E., Peng, Z., Tarr, T. B., Tang, A., Niederst, E. D., Young, J. Z., Tsai, L., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.29.273540 · Cited by 20
Tzioras, M., Daniels, M. J. D., Davies, C., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/795930 · Cited by 20
Paasila, P. J., Davies, D., Sutherland, G. T., & Goldsbury, C. S. (2020) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-2845 · Cited by 16
Ground state depletion microscopy as a tool for studying microglia–synapse interactions
Paasila, P. J., Fok, S., Rodriguez, N. F., Sajjan, S., Svahn, A. J., Dennis, C. V., Holsinger, R. M. D., Kril, J. J., Becker, T. S., Banati, R. B., et al. (2021) · Journal of Neuroscience Research · doi:10.1002/jnr.24819 · Cited by 8
Epitope specificity of anti-synapsin autoantibodies: Differential targeting of synapsin I domains
Mertens, R. G., Melchert, S., Gitler, D., Schou, M. B., Sæther, S. G., Vaaler, A., Piepgras, J., Kochova, E., Benfenati, F., Ahnert‐Hilger, G., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0208636 · Cited by 6
Nanoscale Imaging of Synaptic Connections with Expansion Microscopy
Gallagher, B. R., & Zhao, Y. (2019) · Discoveries · doi:10.15190/d.2019.14 · Cited by 4
Flagged first, then by citations
4 of the 94 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- Doorn, 2014, Increased amoeboid microglial density in the olfactory bulb of Parkinson’s and Alzheimer’s patients., Brain Pathol, 24, 152, 10.1111/bpa.2014.24.issue-2 · DOI
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Cited by
Sorted by citations
de Vries, L. E., Huitinga, I., Kessels, H. W. H. G., Swaab, D. F., & Verhaagen, J. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00719-7 · Cited by 85
Watamura, N., Foiani, M. S., Bez, S., Bourdenx, M., Santambrogio, A., Frodsham, C., Camporesi, E., Brinkmalm, G., Zetterberg, H., Patel, S., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01829-7 · Cited by 67
Self-citationComplement-mediated synapse loss in Alzheimer’s disease: mechanisms and involvement of risk factors
Wen, L., Bi, D., & Shen, Y. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.11.010 · Cited by 64
Promoting Alzheimer’s disease research and therapy with stem cell technology
Cao, Z., Kong, F., Ding, J., Chen, C., He, F., & Deng, W. (2024) · Stem Cell Research & Therapy · doi:10.1186/s13287-024-03737-w · Cited by 60
Malvaso, A., Gatti, A., Negro, G., Calatozzolo, C., Medici, V., & Poloni, T. E. (2023) · Cells · doi:10.3390/cells12242824 · Cited by 54
Metadata
- Authors
- Taddei, R. N., Perbet, R., Mate de Gerando, A., Wiedmer, A. E., Sanchez-Mico, M., Connors Stewart, T., Gaona, A., Melloni, A., Amaral, A. C., Duff, K., Frosch, M. P., & Gómez-Isla, T.
- Affiliations
- Harvard University (US)
- Neurology Department, Massachusetts General Hospital, Harvard University, Boston, Massachusetts
- C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, Massachusetts
- Massachusetts General Hospital (US)
- University College London (GB)
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2023-11-01
- Volume
- 80
- Issue
- 11
- Pages
- 1209
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC10562992
- OpenAlex
- W4387440243
- Cited by
- 110
- References
- 94
- Citations by year
- 2026: 34 · 2025: 46 · 2024: 24 · 2023: 5
- FWCI
- 19.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- National Institute on Aging (R56AG069192)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, tau oligomers, synaptic pruning, microglia, astrocytes, visual cortex, dementia, synaptic density, amyloid plaques, cognitive resilience, expansion microscopy, Iba1, glial fibrillary acidic protein, neuroinflammation, synaptic loss, postmortem brain
- MeSH terms
- Alzheimer Disease, Astrocytes, Child, Cross-Sectional Studies, Female, Humans, Male, Neuroglia, Synapses, Amyloid beta-Peptides, Microglia
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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