APOE ε2 is associated with increased tau pathology in primary tauopathy

Na Zhao, Chia-Chen Liu, Alexandra J. Van Ingelgom, Cynthia Linares, Aishe Kurti, Joshua A. Knight, Michael G. Heckman, Nancy N. Diehl, Mitsuru Shinohara, Yuka A. Martens, Olivia N. Attrebi, Leonard Petrucelli, John D. Fryer, Zbigniew K Wszolek, Neill R Graff Radford, Richard John Caselli, Monica Y. Sanchez-Contreras, Rosa V Rademakers, Melissa E Murray, Shunsuke KogaDennis W Dickson, Owen A Ross, Guojun D Bu

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number4388
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Apolipoprotein E2
Tauopathies
pathology
Pathology
mice
Apolipoprotein E4
Progressive Supranuclear Palsy
Apolipoproteins E
degeneration
Alleles
Genotype
abnormalities
viruses
progressions
genes
Dependovirus
brain
delivery
Viruses
Amyloid

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

APOE ε2 is associated with increased tau pathology in primary tauopathy. / 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 John; Sanchez-Contreras, Monica Y.; Rademakers, Rosa V; Murray, Melissa E; Koga, Shunsuke; Dickson, Dennis W; Ross, Owen A; Bu, Guojun D.

In: Nature Communications, Vol. 9, No. 1, 4388, 01.12.2018.

Research output: Contribution to journalArticle

Zhao, N, Liu, C-C, Van Ingelgom, AJ, Linares, C, Kurti, A, Knight, JA, Heckman, MG, Diehl, NN, Shinohara, M, Martens, YA, Attrebi, ON, Petrucelli, L, Fryer, JD, Wszolek, ZK, Graff Radford, NR, Caselli, RJ, Sanchez-Contreras, MY, Rademakers, RV, Murray, ME, Koga, S, Dickson, DW, Ross, OA & Bu, GD 2018, 'APOE ε2 is associated with increased tau pathology in primary tauopathy', Nature Communications, vol. 9, no. 1, 4388. https://doi.org/10.1038/s41467-018-06783-0
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 John ; Sanchez-Contreras, Monica Y. ; Rademakers, Rosa V ; Murray, Melissa E ; Koga, Shunsuke ; Dickson, Dennis W ; Ross, Owen A ; Bu, Guojun D. / APOE ε2 is associated with increased tau pathology in primary tauopathy. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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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AU - Knight, Joshua A.

AU - Heckman, Michael G.

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AU - Caselli, Richard John

AU - Sanchez-Contreras, Monica Y.

AU - Rademakers, Rosa V

AU - Murray, Melissa E

AU - Koga, Shunsuke

AU - Dickson, Dennis W

AU - Ross, Owen A

AU - Bu, Guojun D

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N2 - 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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