APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

Chia Chen Liu; Melissa E. Murray; Xia Li; Na Zhao; Na Wang; Michael G. Heckman; Francis Shue; Yuka Martens; Yonghe Li; Ana Caroline Raulin; Cassandra L. Rosenberg; Sydney V. Doss; Jing Zhao; Melissa C. Wren; Lin Jia; Yingxue Ren; Tadafumi C. Ikezu; Wenyan Lu; Yuan Fu; Thomas Caulfield; Zachary A. Trottier; Joshua Knight; Yixing Chen; Cynthia Linares; Xue Wang; Aishe Kurti; Yan W. Asmann; Zbigniew K. Wszolek; Glenn E. Smith; Prashanthi Vemuri; Kejal Kantarci; David S. Knopman; Val J. Lowe; Clifford R. Jack; Joseph E. Parisi; Tanis J. Ferman; Bradley F. Boeve; Neill R. Graff-Radford; Ronald C. Petersen; Steven G. Younkin; John D. Fryer; Hu Wang; Xianlin Han; Carl Frieden; Dennis W. Dickson; Owen A. Ross; Guojun Bu

doi:10.1126/scitranslmed.abc9375

APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

Chia Chen Liu, Melissa E. Murray, Xia Li, Na Zhao, Na Wang, Michael G. Heckman, Francis Shue, Yuka Martens, Yonghe Li, Ana Caroline Raulin, Cassandra L. Rosenberg, Sydney V. Doss, Jing Zhao, Melissa C. Wren, Lin Jia, Yingxue Ren, Tadafumi C. Ikezu, Wenyan Lu, Yuan Fu, Thomas CaulfieldZachary A. Trottier, Joshua Knight, Yixing Chen, Cynthia Linares, Xue Wang, Aishe Kurti, Yan W. Asmann, Zbigniew K. Wszolek, Glenn E. Smith, Prashanthi Vemuri, Kejal Kantarci, David S. Knopman, Val J. Lowe, Clifford R. Jack, Joseph E. Parisi, Tanis J. Ferman, Bradley F. Boeve, Neill R. Graff-Radford, Ronald C. Petersen, Steven G. Younkin, John D. Fryer, Hu Wang, Xianlin Han, Carl Frieden, Dennis W. Dickson, Owen A. Ross, Guojun Bu

Research output: Contribution to journal › Article › peer-review

Abstract

Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.

Original language	English (US)
Article number	eabc9375
Journal	Science translational medicine
Volume	13
Issue number	613
DOIs	https://doi.org/10.1126/scitranslmed.abc9375
State	Published - Sep 29 2021

ASJC Scopus subject areas

General Medicine

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Liu, C. C., Murray, M. E., Li, X., Zhao, N., Wang, N., Heckman, M. G., Shue, F., Martens, Y., Li, Y., Raulin, A. C., Rosenberg, C. L., Doss, S. V., Zhao, J., Wren, M. C., Jia, L., Ren, Y., Ikezu, T. C., Lu, W., Fu, Y., ... Bu, G. (2021). APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia. Science translational medicine, 13(613), Article eabc9375. https://doi.org/10.1126/scitranslmed.abc9375

Liu, CC , Murray, ME, Li, X, Zhao, N, Wang, N, Heckman, MG, Shue, F, Martens, Y, Li, Y, Raulin, AC, Rosenberg, CL, Doss, SV, Zhao, J, Wren, MC, Jia, L, Ren, Y, Ikezu, TC, Lu, W, Fu, Y, Caulfield, T, Trottier, ZA, Knight, J, Chen, Y, Linares, C, Wang, X, Kurti, A, Asmann, YW , Wszolek, ZK, Smith, GE, Vemuri, P , Kantarci, K , Knopman, DS , Lowe, VJ , Jack, CR, Parisi, JE, Ferman, TJ , Boeve, BF , Graff-Radford, NR , Petersen, RC , Younkin, SG, Fryer, JD, Wang, H, Han, X, Frieden, C, Dickson, DW , Ross, OA & Bu, G 2021, 'APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia', Science translational medicine, vol. 13, no. 613, eabc9375. https://doi.org/10.1126/scitranslmed.abc9375

@article{09eabf68a791431c87ef320325325de1,

title = "APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia",

abstract = "Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer{\textquoteright}s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.",

author = "Liu, {Chia Chen} and Murray, {Melissa E.} and Xia Li and Na Zhao and Na Wang and Heckman, {Michael G.} and Francis Shue and Yuka Martens and Yonghe Li and Raulin, {Ana Caroline} and Rosenberg, {Cassandra L.} and Doss, {Sydney V.} and Jing Zhao and Wren, {Melissa C.} and Lin Jia and Yingxue Ren and Ikezu, {Tadafumi C.} and Wenyan Lu and Yuan Fu and Thomas Caulfield and Trottier, {Zachary A.} and Joshua Knight and Yixing Chen and Cynthia Linares and Xue Wang and Aishe Kurti and Asmann, {Yan W.} and Wszolek, {Zbigniew K.} and Smith, {Glenn E.} and Prashanthi Vemuri and Kejal Kantarci and Knopman, {David S.} and Lowe, {Val J.} and Jack, {Clifford R.} and Parisi, {Joseph E.} and Ferman, {Tanis J.} and Boeve, {Bradley F.} and Graff-Radford, {Neill R.} and Petersen, {Ronald C.} and Younkin, {Steven G.} and Fryer, {John D.} and Hu Wang and Xianlin Han and Carl Frieden and Dickson, {Dennis W.} and Ross, {Owen A.} and Guojun Bu",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Authors, some rights reserved;",

year = "2021",

month = sep,

day = "29",

doi = "10.1126/scitranslmed.abc9375",

language = "English (US)",

volume = "13",

journal = "Science translational medicine",

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publisher = "American Association for the Advancement of Science",

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T1 - APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

AU - Liu, Chia Chen

AU - Murray, Melissa E.

AU - Li, Xia

AU - Zhao, Na

AU - Wang, Na

AU - Heckman, Michael G.

AU - Shue, Francis

AU - Martens, Yuka

AU - Li, Yonghe

AU - Raulin, Ana Caroline

AU - Rosenberg, Cassandra L.

AU - Doss, Sydney V.

AU - Zhao, Jing

AU - Wren, Melissa C.

AU - Jia, Lin

AU - Ren, Yingxue

AU - Ikezu, Tadafumi C.

AU - Lu, Wenyan

AU - Fu, Yuan

AU - Caulfield, Thomas

AU - Trottier, Zachary A.

AU - Knight, Joshua

AU - Chen, Yixing

AU - Linares, Cynthia

AU - Wang, Xue

AU - Kurti, Aishe

AU - Asmann, Yan W.

AU - Wszolek, Zbigniew K.

AU - Smith, Glenn E.

AU - Vemuri, Prashanthi

AU - Kantarci, Kejal

AU - Knopman, David S.

AU - Lowe, Val J.

AU - Jack, Clifford R.

AU - Parisi, Joseph E.

AU - Ferman, Tanis J.

AU - Boeve, Bradley F.

AU - Graff-Radford, Neill R.

AU - Petersen, Ronald C.

AU - Younkin, Steven G.

AU - Fryer, John D.

AU - Wang, Hu

AU - Han, Xianlin

AU - Frieden, Carl

AU - Dickson, Dennis W.

AU - Ross, Owen A.

AU - Bu, Guojun

PY - 2021/9/29

Y1 - 2021/9/29

N2 - Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.

AB - Apolipoprotein E (APOE) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant (APOE3-V236E), named APOE3-Jacksonville (APOE3-Jac), associated with healthy brain aging and reduced risk for AD and dementia with Lewy bodies (DLB). Herein, we resolved the functional mechanism by which APOE3-Jac reduces APOE aggregation and enhances its lipidation in human brains, as well as in cellular and biochemical assays. Compared to APOE3, expression of APOE3-Jac in astrocytes increases several classes of lipids in the brain including phosphatidylserine, phosphatidylethanolamine, phosphatidic acid, and sulfatide, critical for synaptic functions. Mice expressing APOE3-Jac have reduced amyloid pathology, plaque-associated immune responses, and neuritic dystrophy. The V236E substitution is also sufficient to reduce the aggregation of APOE4, whose gene allele is a major genetic risk factor for AD and DLB. These findings suggest that targeting APOE aggregation might be an effective strategy for treating a subgroup of individuals with AD and DLB.

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AN - SCOPUS:85117112693

SN - 1946-6234

VL - 13

JO - Science translational medicine

JF - Science translational medicine

IS - 613

M1 - eabc9375

ER -

APOE3-Jacksonville (V236E) variant reduces self-aggregation and risk of dementia

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