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

被引：65

作者：

Liu, Chia-Chen ^{[1
]}

Murray, Melissa E. ^{[1
]}

Li, Xia ^{[1
]}

Zhao, Na ^{[1
]}

Wang, Na ^{[1
]}

Heckman, Michael G. ^{[2
]}

Shue, Francis ^{[1
]}

Martens, Yuka ^{[1
]}

Li, Yonghe ^{[1
]}

Raulin, Ana-Caroline ^{[1
]}

Rosenberg, Cassandra L. ^{[1
]}

Doss, Sydney, V ^{[1
]}

Zhao, Jing ^{[1
]}

Wren, Melissa C. ^{[1
]}

Jia, Lin ^{[1
]}

Ren, Yingxue ^{[2
]}

Ikezu, Tadafumi C. ^{[1
]}

Lu, Wenyan ^{[1
]}

Fu, Yuan ^{[1
]}

Caulfield, Thomas ^{[1
]}

Trottier, Zachary A. ^{[1
]}

Knight, Joshua ^{[1
]}

Chen, Yixing ^{[1
]}

Linares, Cynthia ^{[1
]}

Wang, Xue ^{[2
]}

Kurti, Aishe ^{[1
]}

Asmann, Yan W. ^{[2
]}

Wszolek, Zbigniew K. ^{[3
]}

Smith, Glenn E. ^{[4
]}

Vemuri, Prashanthi ^{[5
]}

Kantarci, Kejal ^{[5
]}

Knopman, David S. ^{[6
]}

Lowe, Val J. ^{[5
]}

Jack, Clifford R. Jr Jr ^{[5
]}

Parisi, Joseph E. ^{[6
,7
]}

Ferman, Tanis J. ^{[8
]}

Boeve, Bradley F. ^{[6
]}

Graff-Radford, Neill R. ^{[3
]}

Petersen, Ronald C. ^{[6
]}

Younkin, Steven G. ^{[1
]}

Fryer, John D. ^{[9
]}

Wang, Hu ^{[10
]}

Han, Xianlin ^{[10
,11
]}

Frieden, Carl ^{[12
]}

Dickson, Dennis W. ^{[1
]}

Ross, Owen A. ^{[1
,13
]}

Bu, Guojun ^{[1
]}

机构：

[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Mayo Clin, Div Biomed Stat & Informat, Dept Hlth Sci Res, Jacksonville, FL 32224 USA

[3] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[4] Mayo Clin, Dept Psychiat & Psychol, Rochester, MN 55905 USA

[5] Mayo Clin, Dept Radiol, Rochester, MN 55905 USA

[6] Mayo Clin, Dept Neurol, Rochester, MN 55905 USA

[7] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA

[8] Mayo Clin, Dept Psychiat & Psychol, Jacksonville, FL 32224 USA

[9] Mayo Clin, Dept Neurosci, Scottsdale, AZ 85259 USA

[10] Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA

[11] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA

[12] Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA

[13] Mayo Clin, Dept Clin Genom, Jacksonville, FL 32224 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2021年 / 13卷 / 613期

关键词：

MULTIDIMENSIONAL MASS-SPECTROMETRY; HEPARAN-SULFATE PROTEOGLYCANS; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; APOE; BINDING; PROTEIN; IDENTIFICATION; DEPOSITION; INCREASES;

D O I：

10.1126/scitranslmed.abc9375

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：11

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