Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody
Open accessAbstract
Microglia have been shown to contribute to the clearance of brain amyloid β peptides (Aβ), the major component of amyloid plaques, in Alzheimer’s disease (AD). However, it is not known whether microglia play a similar role in the clearance of tau, the major component of neurofibrillary tangles (NFTs). We now report that murine microglia rapidly internalize and degrade hyperphosphorylated pathological tau isolated from AD brain tissue in a time-dependent manner in vitro. We further demonstrate that microglia readily degrade human tau species released from AD brain sections and eliminate NFTs from brain sections of P301S tauopathy mice. The anti-tau monoclonal antibody MC1 enhances microglia-mediated tau degradation in an Fc-dependent manner. Our data identify a potential role for microglia in the degradation and clearance of pathological tau species in brain and provide a mechanism explaining the potential therapeutic actions of passively administered anti-tau monoclonal antibodies.
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Microglia have a preponderant role in the spread of pathological tau throughout the brain.
“supporting a preponderant role of microglia in the spread of pathological tau throughout the brain [23,34,35,36].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [36]
The Discussion says impaired microglial clearance of tau may allow its accumulation and inter-neuronal spread, so the paper links microglia to spread indirectly. It presents this as a hypothesis requiring in vivo validation, not as evidence that microglia have a preponderant role in spreading pathological tau throughout the brain. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglia can phagocytose extracellular pathological tau.
“Given that microglia can phagocytose extracellular pathological tau [148, 149], and that tau misfolds and acquires toxic gain-of-function properties in our vascular amyloid model [120], tau ablation likely reduces this pathological burden.”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [149]
Microglia can actively phagocytize tau.
“Multiple studies have demonstrated that microglia can actively phagocytize tau”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [36]
Microglia directly promote tau clearance through internalizing and degrading pathological tau from AD brain.
“For example, microglia can directly promote tau clearance through internalizing and degrading pathological tau from AD brain [428], where mechanisms underlying this phenomenon remain elusive.”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [428]
Once engulfed, tau is either degraded or re-released in exosomes.
“Once engulfed, tau is either degraded [116] or re-released in exocytosing microvesicles called exosomes [7, 55].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [116]
Microglia readily take up both soluble and insoluble forms of tau.
“Microglia readily take up both soluble and insoluble forms of tau [7, 56, 82, 116].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [116]
Some studies have reported that microglia can mediate tau clearance and this is enhanced with tau monoclonal antibody treatment.
“Some studies have reported that microglia can mediate tau clearance and this is enhanced with tau monoclonal antibody treatment [116, 181].”
From Glial contributions to neurodegeneration in tauopathies (2017) · cites this paper as [116]
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- Authors
- Luo, W., Liu, W., Hu, X., Hanna, M., Caravaca, A., & Paul, S. M.
- Affiliations
- Cornell University (US)
- Corresponding author
- Luo, Wenjie
- Paul, Steven M.
- Venue
- Scientific Reports
- Published
- 2015-06-09
- Volume
- 5
- Issue
- 1
- Pages
- 11161-11161
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4460904
- OpenAlex
- W2172969782
- Cited by
- 241
- References
- 48
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 26 · 2023: 22 · 2022: 42 · 2021: 33 · 2020: 34 · 2019: 17 · 2018: 23 · 2017: 12 · 2016: 9 · 2015: 1
- FWCI
- 11.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Eli Lilly and Company
- University of Pennsylvania
- Topics
- Health Sciences › Medicine › Physiology › 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
- microglia, pathological tau, tau clearance, neurofibrillary tangles, hyperphosphorylated tau, Alzheimer's disease, passive immunotherapy
- MeSH terms
- Alzheimer Disease, Animals, Antibodies, Monoclonal, tau Proteins, Microglia, Mice, Proteolysis
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