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

Autor:	Liu CC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Murray ME; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Li X; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Zhao N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Wang N; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Heckman MG; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA., Shue F; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Martens Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Li Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Raulin AC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Rosenberg CL; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Doss SV; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Zhao J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Wren MC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Jia L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Ren Y; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA., Ikezu TC; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Lu W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Fu Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Caulfield T; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Trottier ZA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Knight J; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Chen Y; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Linares C; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Wang X; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA., Kurti A; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Asmann YW; Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL 32224, USA., Wszolek ZK; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Smith GE; Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN 55905, USA., Vemuri P; Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA., Kantarci K; Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA., Knopman DS; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA., Lowe VJ; Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA., Jack CR Jr; Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA., Parisi JE; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA., Ferman TJ; Department of Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL 32224, USA., Boeve BF; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA., Graff-Radford NR; Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA., Petersen RC; Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA., Younkin SG; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Fryer JD; Department of Neuroscience, Mayo Clinic, Scottsdale, AZ 85259, USA., Wang H; Barshop Institute for Longevity and Aging Studies, San Antonio, TX 78229, USA., Han X; Barshop Institute for Longevity and Aging Studies, San Antonio, TX 78229, USA.; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA., Frieden C; Department of Biochemistry and Molecular Biophysics, Washington University, St. Louis, MO 63110, USA., Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA., Ross OA; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA., Bu G; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2021 Sep 29; Vol. 13 (613), pp. eabc9375. Date of Electronic Publication: 2021 Sep 29.
DOI:	10.1126/scitranslmed.abc9375
Abstrakt:	Apolipoprotein E ( APOE ) genetic variants have been shown to modify Alzheimer’s disease (AD) risk. We previously identified an APOE3 variant ( APOE 3-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.
Databáze:	MEDLINE
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