Distinct Therapeutic Mechanisms of Tau Antibodies
Open accessAbstract
Tauopathies are neurodegenerative diseases characterized by accumulation of Tau amyloids, and include Alzheimer disease and certain frontotemporal dementias. Trans-neuronal propagation of amyloid mediated by extracellular Tau may underlie disease progression. Consistent with this, active and passive vaccination studies in mouse models reduce pathology, although by unknown mechanisms. We previously reported that intracerebroventricular administration of three anti-Tau monoclonal antibodies (HJ8.5, HJ9.3, and HJ9.4) reduces pathology in a model overexpressing full-length mutant (P301S) human Tau. We now study effects of these three antibodies and a negative control antibody (HJ3.4) on Tau aggregate uptake into BV2 microglial-like cells and primary neurons. Antibody-independent Tau uptake into BV2 cells was blocked by heparin, consistent with a previously described role for heparan sulfate proteoglycans. Two therapeutic antibodies (HJ8.5 and HJ9.4) promoted uptake of full-length Tau fibrils into microglia via Fc receptors. Surprisingly, HJ9.3 promoted uptake of fibrils composed of the Tau repeat domain or Alzheimer disease-derived Tau aggregates, but failed to influence full-length recombinant Tau fibrils. Size fractionation of aggregates showed that antibodies preferentially promote uptake of larger oligomers (n ≥ ∼ 20-mer) versus smaller oligomers (n ∼ 10-mer) or monomer. No antibody inhibited uptake of full-length recombinant fibrils into primary neurons, but HJ9.3 blocked neuronal uptake of Tau repeat domain fibrils and Alzheimer disease-derived Tau. Antibodies thus have multiple potential mechanisms, including clearance via microglia and blockade of neuronal uptake. However these effects are epitope- and aggregate size-dependent. Establishing specific mechanisms of antibody activity in vitro may help in design and optimization of agents that are more effective in vivo.
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Microglia can internalise aggregated or hyperphosphorylated tau for degradation, but can also release incompletely degraded forms into extracellular space, promoting tau spread.
“human and microglia can internalise aggregated or hyperphosphorylated tau for protein degradation, they can also release incompletely degraded or un-neutralised forms back it into the extracellular space, promoting the spread of tau [12, 32, 36, 108, 153]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [108]
The Results report uptake of tau aggregates by BV2 microglial cells, and the introductory discussion describes microglial phagocytosis of tau oligomers. The paper does not establish that microglia degrade the internalised tau or release incompletely degraded tau that promotes spread; its account of extracellular tau spreading instead describes release from diseased neurons. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSome 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 [181]
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- Authors
- Funk, K. E., Mirbaha, H., Jiang, H., Holtzman, D. M., & Diamond, M. I.
- Affiliations
- Washington University in St. Louis (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Diamond, Marc I.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 290
- Issue
- 35
- Pages
- 21652-21662
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4571888
- OpenAlex
- W1946081631
- Cited by
- 111
- References
- 47
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 11 · 2020: 13 · 2019: 14 · 2018: 17 · 2017: 12 · 2016: 12 · 2015: 2
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1R01NS071835, P50AG005681, P01AG003991)
- 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
- tauopathy, Alzheimer's disease, frontotemporal dementia, Fc receptors, heparan sulfate proteoglycans, tau repeat domain, passive immunization, P301S tau
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Antibodies, Cell Line, Cerebral Cortex, Humans, Neurons, tau Proteins, Protein Structure, Tertiary, Receptors, IgG, Microglia, Heparan Sulfate Proteoglycans, Mice
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