ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S et al.. Nature, 2017-09-20
Topic: Brain proteins, microglia and lab models
APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.
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APA 7th
Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., et al. (2017). ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. https://doi.org/10.1038/nature24016
Vancouver
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature. 2017. doi:10.1038/nature24016. PMID: 28959956.
BibTeX
@article{shi2017-28959956,
author = {Shi, Y. and Yamada, K. and Liddelow, S. A. and Smith, S. T. and Zhao, L. and Luo, W. and Tsai, R. M. and Spina, S. and others},
title = {{ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy}},
journal = {Nature},
year = {2017},
doi = {10.1038/nature24016},
pmid = {28959956},
url = {https://doi.org/10.1038/nature24016}
}
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Key findings
- By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice.
- Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures.
- Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect.
- In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration.
- Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology.
Why it matters
In mice engineered to develop tau damage, those carrying the human APOE4 gene version had more tau, more brain shrinkage and more inflammation than mice with APOE2 or APOE3, while mice with no APOE were "largely protected"; in lab dishes, APOE4 support cells released more of the inflammatory signal TNF-α and killed more neurons. The authors conclude that APOE affects tau-driven damage "independently of amyloid-β", and report that in people, carrying ε4 "is associated with" more severe brain degeneration in one tau disease and faster progression in Alzheimer's. These are animal, cell and association findings with no treatment tested, so they point to a possible mechanism but do not show that targeting APOE4 would treat or prevent Alzheimer's in people.
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Study details
- Evidence strengthLow
How this study scored 65/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 2 / 5 | 2017 — within 10 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mouse”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 1,220 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 110.9 citations a year over 11 year(s) since 2017 |
| Impact for its field and year | 6 / 6 | Cited 65.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 88 other studies in this library |
| Still being cited | 4 / 4 | Cited 379 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 4 / 4 | Last-listed author David M. Holtzman: h-index 206 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 16 institution(s) in 3 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 28959956) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 65 / 100 | — |
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