TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss
Open accessAbstract
Microglia coordinate various functions in the central nervous system ranging from removing synaptic connections, to maintaining brain homeostasis by monitoring neuronal function, and clearing protein aggregates across the lifespan. Here we investigated whether increased microglial phagocytic activity that clears amyloid can also cause pathological synapse loss. We identified TDP-43, a DNA-RNA binding protein encoded by the Tardbp gene, as a strong regulator of microglial phagocytosis. Mice lacking TDP-43 in microglia exhibit reduced amyloid load in a model of Alzheimer's disease (AD) but at the same time display drastic synapse loss, even in the absence of amyloid. Clinical examination from TDP-43 pathology cases reveal a considerably reduced prevalence of AD and decreased amyloid pathology compared to age-matched healthy controls, confirming our experimental results. Overall, our data suggest that dysfunctional microglia might play a causative role in the pathogenesis of neurodegenerative disorders, critically modulating the early stages of cognitive decline.
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Tardbp is protective against synapse loss in an Alzheimer's disease mouse model, whereas its absence promotes higher amyloid clearance by enhancing phagocytosis.
“Tardbp has been shown recently to be protective against synapse loss in an AD mouse model, whereas its absence promotes higher amyloid clearance by enhancing phagocytosis”
From Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program (2019) · cites this paper as Paolicelli et al., 2017
Quantification of internalized PSD95 in individual microglia in the dentate gyrus showed an increase in steady-state internal PSD95 in XO4− microglia compared to XO4+ microglia (p = 0.0057).
“Quantification of the internalized post-synaptic marker, PSD9546, in individual microglia in the dentate gyrus of WT and 5xFAD mice (Fig. 4a and Supplementary Fig. 10a) showed an increase in steady-state internal PSD95 in XO4− microglia compared to XO4+ microglia (Fig. 4b; p = 0.0057, one-way ANOVA and Tukey’s multiple comparison test).”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [46]
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Grubman, A., Choo, X. Y., Chew, G., Ouyang, J. F., Sun, G., Croft, N. P., Rossello, F. J., Simmons, R., Buckberry, S., Landin, D. V., et al. (2019) · doi:10.1101/639054 · Cited by 7 · see citing works
- Authors
- Paolicelli, R. C., Jawaid, A., Henstridge, C. M., Valeri, A., Merlini, M., Robinson, J. L., Lee, E. B., Rose, J., Appel, S., Lee, V. M.-Y., Trojanowski, J. Q., Spires-Jones, T., Schulz, P. E., & Rajendran, L.
- Affiliations
- University of Zurich (CH)
- University of Edinburgh (GB)
- University of Pennsylvania (US)
- Houston Methodist (US)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Paolicelli, Rosa C.
- Rajendran, Lawrence
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 95
- Issue
- 2
- Pages
- 297-308.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5519492
- OpenAlex
- W2732599352
- Cited by
- 239
- References
- 20
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 37 · 2023: 21 · 2022: 32 · 2021: 29 · 2020: 30 · 2019: 21 · 2018: 25 · 2017: 8
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuron (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc-nd)
- Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by-nc-nd)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-nd)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc-nd)
- ETH Zürich Research Collection
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Swiss National Science Foundation (SNF)
- Synapsis Foundation Alzheimer Research Switzerland ARS
- Velux Stiftung
- Cure Alzheimer Fund
- Sinergia
- Interdisciplinary Core
- Forschungskredit University of Zurich
- Alzheimer’s Research UK, European Research Council
- MND Scotland
- Motor Neurone Disease Scotland
- European Research Council (ALZSYN)
- Alzheimer’s Research UK
- Scottish Government Chief Scientist Office
- Wellcome Trust-University of Edinburgh Institutional Strategic Support Fund
- Alzheimer's Society
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- TDP-43, microglia, microglial phagocytosis, amyloid clearance, synaptic loss, Alzheimer's disease, TARDBP, neurodegeneration, cognitive decline, protein aggregate clearance
- MeSH terms
- Amyloid, Amyotrophic Lateral Sclerosis, Animals, Brain, Cognition, DNA-Binding Proteins, Mice, Transgenic, Synapses, Microglia
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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.
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