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Cited by 142Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchParkinson's Disease Mechanisms and Treatments

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APOE ε2 is associated with increased tau pathology in primary tauopathy

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Zhao, Na, Liu, Chia-Chen, Van Ingelgom, Alexandra J., Linares, Cynthia, Kurti, Aishe, Knight, Joshua A., Heckman, Michael G., Diehl, Nancy N., Shinohara, Mitsuru, Martens, Yuka A., Attrebi, Olivia N., Petrucelli, Leonard, Fryer, John D., Wszolek, Zbigniew K., Graff-Radford, Neill R., Caselli, Richard J., Sanchez-Contreras, Monica Y., Rademakers, Rosa, Murray, Melissa E., Koga, Shunsuke, Dickson, Dennis W., Ross, Owen A., Bu, Guojun·2018·Nature Communications
DOI 10.1038/s41467-018-06783-0PMC PMC6197187
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Abstract

Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by modulating amyloid-β pathology. APOE ε4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE ε2/ε2. We also show that in humans, the APOE ε2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ε2/ε2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ε2 status may influence the risk and progression of tauopathy.

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Figures

Fig. 1 Increased hyperphosphorylated tau species, thioflavin S-positive tau aggregates, and related astrogliosis in TauP301L-apoE2 mice. Brain slices from AAV-GFP control mice (Ctrl) and AAV-TauP301L-apoE2, -apoE3, and -apoE4 mice were prepared. The hyperphophorylated tau, aggregated tau, and astrogliosis were determined by AT8, thioflavin S, and GFAP staining at 6 months of age. a Representative images are shown for the deposition of AT8-positive tau species, thioflavin S-positive tau aggregates, and astrogliosis in the cortex (the region above hippocampus) of control (Ctrl) and TauP301L-apoE2, -apoE3, and -apoE4 mice at 6 months of age. Scale bar, 100 μm. The immunoreactivity of AT8 staining (b), thioflavin S staining (c), and GFAP staining (d) was evaluated by Aperio ImageScope (n = 6 mice per group, mixed gender). Data represent mean ± SEM. Mann-Whitney tests followed by Bonferroni correction for multiple comparisons were used. *P < 0.0167; N.S. not significant
Fig. 1 Increased hyperphosphorylated tau species, thioflavin S-positive tau aggregates, and related astrogliosis in TauP301L-apoE2 mice. Brain slices from AAV-GFP control mice (Ctrl) and AAV-TauP301L-apoE2, -apoE3, and -apoE4 mice were prepared. The hyperphophorylated tau, aggregated tau, and astrogliosis were determined by AT8, thioflavin S, and GFAP staining at 6 months of age. a Representative images are shown for the deposition of AT8-positive tau species, thioflavin S-positive tau aggregates, and astrogliosis in the cortex (the region above hippocampus) of control (Ctrl) and TauP301L-apoE2, -apoE3, and -apoE4 mice at 6 months of age. Scale bar, 100 μm. The immunoreactivity of AT8 staining (b), thioflavin S staining (c), and GFAP staining (d) was evaluated by Aperio ImageScope (n = 6 mice per group, mixed gender). Data represent mean ± SEM. Mann-Whitney tests followed by Bonferroni correction for multiple comparisons were used. *P < 0.0167; N.S. not significantCC BY · PubMed Central
Fig. 2 Behavioral abnormalities and compromised synaptic integrity in TauP301L-apoE2 mice. Behavioral performance was assessed in control mice (Ctrl, AAV-GFP-injected, n = 12 mice per group, mixed gender) and TauP301L-apoE2, -apoE3, and -apoE4 mice (n = 13 mice for TauP301L-apoE2 group, n = 20 mice for TauP301L-apoE3 group, n = 22 mice for TauP301L-apoE4 group, mixed gender) at 6 months of age. a Open-field analysis was assessed and the ratios of time spent in the center quadrant to total distance traveled in the open-field apparatus are shown. b Exploratory behavior was evaluated in the elevated plus maze and the ratios of the time spent in open arms to close arms are shown. c, d Fear conditioning test was utilized to examine the associative memory. The percentage of the time with freezing behavior in response to stimulus during context (c) and cued (d) tests is shown. Data represent mean ± SEM. e–g The amount of GluR2 and PSD95 in the cortical RIPA lysate was examined by western blotting for control mice and TauP301L-apoE mice (n = 6 mice per group, mixed gender) at 6 months of age. Results were normalized to β-actin levels. Data are expressed as mean ± SEM. Mann-Whitney tests followed by Bonferroni correction for multiple comparisons were used. *P < 0.0167; N.S. not significant
Fig. 2 Behavioral abnormalities and compromised synaptic integrity in TauP301L-apoE2 mice. Behavioral performance was assessed in control mice (Ctrl, AAV-GFP-injected, n = 12 mice per group, mixed gender) and TauP301L-apoE2, -apoE3, and -apoE4 mice (n = 13 mice for TauP301L-apoE2 group, n = 20 mice for TauP301L-apoE3 group, n = 22 mice for TauP301L-apoE4 group, mixed gender) at 6 months of age. a Open-field analysis was assessed and the ratios of time spent in the center quadrant to total distance traveled in the open-field apparatus are shown. b Exploratory behavior was evaluated in the elevated plus maze and the ratios of the time spent in open arms to close arms are shown. c, d Fear conditioning test was utilized to examine the associative memory. The percentage of the time with freezing behavior in response to stimulus during context (c) and cued (d) tests is shown. Data represent mean ± SEM. e–g The amount of GluR2 and PSD95 in the cortical RIPA lysate was examined by western blotting for control mice and TauP301L-apoE mice (n = 6 mice per group, mixed gender) at 6 months of age. Results were normalized to β-actin levels. Data are expressed as mean ± SEM. Mann-Whitney tests followed by Bonferroni correction for multiple comparisons were used. *P < 0.0167; N.S. not significantCC BY · PubMed Central
Fig. 3 Increased insolubility of tau and apoE in TauP301L-apoE2 mice. The cortical brain tissues from control mice (Ctrl, AAV-GFP-injected) and TauP301L-apoE2, -apoE3, and -apoE4 mice at 6 months of age were sequentially extracted by RAB, RIPA, and FA buffer. Soluble tau (HT7 detection) and apoE in RAB (a, b) and RIPA fractions (a, c) were examined by western blotting (n = 6 mice per group, mixed gender). Results were normalized to β-actin levels. Insoluble tau and apoE in FA fraction was detected by ELISA (d n = 6 mice per group, mixed gender). Data are expressed as mean ± SEM relative to apoE2-TR mice. Mann-Whitney tests followed by Bonferroni correction for multiple comparisons were used. *P < 0.0167; N.S. not significant
Fig. 3 Increased insolubility of tau and apoE in TauP301L-apoE2 mice. The cortical brain tissues from control mice (Ctrl, AAV-GFP-injected) and TauP301L-apoE2, -apoE3, and -apoE4 mice at 6 months of age were sequentially extracted by RAB, RIPA, and FA buffer. Soluble tau (HT7 detection) and apoE in RAB (a, b) and RIPA fractions (a, c) were examined by western blotting (n = 6 mice per group, mixed gender). Results were normalized to β-actin levels. Insoluble tau and apoE in FA fraction was detected by ELISA (d n = 6 mice per group, mixed gender). Data are expressed as mean ± SEM relative to apoE2-TR mice. Mann-Whitney tests followed by Bonferroni correction for multiple comparisons were used. *P < 0.0167; N.S. not significantCC BY · PubMed Central
Fig. 4 Disulfide bond-mediated complex formation between tau and apoE in vitro. The in vitro interaction between tau and apoE proteins was evaluated by solution binding assay, followed by western blotting (four independent experiments). Recombinant human apoE protein was incubated with tau protein for 1 h at 37 °C in 20 µl of phosphate-buffered saline. The reaction was quenched by addition of 20 µl of sample buffer without (lane 1–7) or with (lane 8–10) reducing agent 2-mercaptoethanol (2-ME). a The presence of tau/apoE complexes (bands A and B) were determined by immunoblotting with antibodies to tau and apoE, respectively. The amounts of tau (b) and apoE (c) in the tau/apoE complexes were quantified. Bands A and B were tau/apoE complexes. Band C was a nonspecific band from tau immunoblot. Bands D and F were monomeric tau and apoE, respectively. Band E was estimated to be apoE dimer. Data are expressed as mean ± SEM relative to apoE2 condition. One-way ANOVA with Tukey post hoc tests were used. *P < 0.05; N.S. not significant
Fig. 4 Disulfide bond-mediated complex formation between tau and apoE in vitro. The in vitro interaction between tau and apoE proteins was evaluated by solution binding assay, followed by western blotting (four independent experiments). Recombinant human apoE protein was incubated with tau protein for 1 h at 37 °C in 20 µl of phosphate-buffered saline. The reaction was quenched by addition of 20 µl of sample buffer without (lane 1–7) or with (lane 8–10) reducing agent 2-mercaptoethanol (2-ME). a The presence of tau/apoE complexes (bands A and B) were determined by immunoblotting with antibodies to tau and apoE, respectively. The amounts of tau (b) and apoE (c) in the tau/apoE complexes were quantified. Bands A and B were tau/apoE complexes. Band C was a nonspecific band from tau immunoblot. Bands D and F were monomeric tau and apoE, respectively. Band E was estimated to be apoE dimer. Data are expressed as mean ± SEM relative to apoE2 condition. One-way ANOVA with Tukey post hoc tests were used. *P < 0.05; N.S. not significantCC BY · PubMed Central

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  1. Dickson, D. W., Hauw, J.-J., Agid, Y. and Litvan, I. in Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders 2nd edn (eds Dickon, D. W. & Weller, R. O.) Ch. 15 (Wiley-Blackwell, Chichester, 2011).

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Metadata

Authors
Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Linares, C., Kurti, A., Knight, J. A., Heckman, M. G., Diehl, N. N., Shinohara, M., Martens, Y. A., Attrebi, O. N., Petrucelli, L., Fryer, J. D., Wszolek, Z. K., Graff-Radford, N. R., Caselli, R. J., Sanchez-Contreras, M. Y., Rademakers, R., Murray, M. E., Koga, S., Dickson, D. W., Ross, O. A., & Bu, G.
Affiliations
  • Mayo Clinic (US)
  • Mayo Clinic in Florida (US)
Corresponding author
  • Liu, Chia-Chen
  • Bu, Guojun
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2018-10-22
Volume
9
Issue
1
Pages
4388-4388
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-018-06783-0
PMC
PMC6197187
OpenAlex
W2897709706
Cited by
139
References
59
Citations by year
2026: 14 · 2025: 11 · 2024: 13 · 2023: 15 · 2022: 20 · 2021: 20 · 2020: 30 · 2019: 15 · 2018: 1
FWCI
11.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (R01AG046205, R37AG027924, RF1AG051504, P50AG016574)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
APOE ε2, apolipoprotein E, tau pathology, primary tauopathies, progressive supranuclear palsy, corticobasal degeneration, tau hyperphosphorylation, tau aggregates, AAV gene delivery, genetic risk, neurodegeneration, behavioral abnormalities
MeSH terms
Alleles, Alzheimer Disease, Animals, Humans, Supranuclear Palsy, Progressive, Disease Progression, Tauopathies, Mice, Apolipoprotein E4, Apolipoprotein E2

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