Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

被引:904
作者
Castellano, Joseph M. [1 ,2 ,3 ]
Kim, Jungsu [1 ,2 ,3 ]
Stewart, Floy R. [1 ,2 ,3 ]
Jiang, Hong [1 ,2 ,3 ]
DeMattos, Ronald B. [4 ]
Patterson, Bruce W. [5 ]
Fagan, Anne M. [1 ,2 ,3 ]
Morris, John C. [1 ,3 ]
Mawuenyega, Kwasi G. [1 ,2 ,3 ]
Cruchaga, Carlos [2 ,3 ,6 ]
Goate, Alison M. [1 ,2 ,3 ,6 ]
Bales, Kelly R. [7 ]
Paul, Steven M. [8 ]
Bateman, Randall J. [1 ,2 ,3 ]
Holtzman, David M. [1 ,2 ,3 ,9 ]
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA
[3] Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimers Dis Res Ctr, St Louis, MO 63110 USA
[4] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA
[5] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA
[6] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA
[7] Pfizer Global Res & Dev, Neurosci Res Unit, Groton, CT 06430 USA
[8] Cornell Univ, Appel Alzheimers Dis Res Inst, Weill Cornell Med Coll, New York, NY 10065 USA
[9] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA
关键词
CEREBROSPINAL-FLUID A-BETA(42); DENSITY-LIPOPROTEIN RECEPTOR; APOLIPOPROTEIN-E; ALZHEIMERS-DISEASE; MOUSE MODEL; FIBRIL FORMATION; CELL-CULTURE; DEPOSITION; BINDING; MICRODIALYSIS;
D O I
10.1126/scitranslmed.3002156
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The apolipoprotein E (APOE) epsilon 4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE epsilon 4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-beta (A beta) peptide. In contrast, the APOE epsilon 2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of A beta(42) peptide. However, the mechanism by which APOE alleles differentially modulate A beta accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral A beta deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect A beta clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of A beta accumulation later in life. Performing in vivo microdialysis in a mouse model of A beta-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble A beta in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of A beta deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble A beta metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of A beta deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and A beta synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of A beta from the brain, suggesting that A beta clearance pathways may be useful therapeutic targets for AD prevention.
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页数:11
相关论文
共 65 条
[1]   Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease [J].
Aleshkov, S ;
Abraham, CR ;
Zannis, VI .
BIOCHEMISTRY, 1997, 36 (34) :10571-10580
[2]   Human APOE Isoform-Dependent Effects on Brain β-Amyloid Levels in PDAPP Transgenic Mice [J].
Bales, Kelly R. ;
Liu, Feng ;
Wu, Su ;
Lin, Suizhen ;
Koger, Deanna ;
DeLong, Cynthia ;
Hansen, Jeffrey C. ;
Sullivan, Patrick M. ;
Paul, Steven M. .
JOURNAL OF NEUROSCIENCE, 2009, 29 (21) :6771-6779
[3]   Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition [J].
Bales, KR ;
Verina, T ;
Dodel, RC ;
Du, YS ;
Altstiel, L ;
Bender, M ;
Hyslop, P ;
Johnstone, EM ;
Little, SP ;
Cummins, DJ ;
Piccardo, P ;
Ghetti, B ;
Paul, SM .
NATURE GENETICS, 1997, 17 (03) :263-264
[4]   Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo [J].
Bateman, Randall J. ;
Munsell, Ling Y. ;
Morris, John C. ;
Swarm, Robert ;
Yarasheski, Kevin E. ;
Holtzman, David M. .
NATURE MEDICINE, 2006, 12 (07) :856-861
[5]   ApoE associated with lipid has a reduced capacity to inhibit β-amyloid fibril formation [J].
Beffert, U ;
Poirier, J .
NEUROREPORT, 1998, 9 (14) :3321-3323
[6]  
Beffert U, 1998, J NEUROCHEM, V70, P1458
[7]   Transport pathways for clearance of human Alzheimer's amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system [J].
Bell, Robert D. ;
Sagare, Abhay P. ;
Friedman, Alan E. ;
Bedi, Gurrinder S. ;
Holtzman, David M. ;
Deane, Rashid ;
Zlokovic, Berislav V. .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2007, 27 (05) :909-918
[8]   Co-expression of beta-amyloid precursor protein (beta APP) and apolipoprotein E in cell culture: Analysis of beta APP processing [J].
Biere, AL ;
Ostaszewski, B ;
Zhao, HW ;
Gillespie, S ;
Younkin, SG ;
Selkoe, DJ .
NEUROBIOLOGY OF DISEASE, 1995, 2 (03) :177-187
[9]   Amyloid-β dynamics correlate with neurological status in the injured human brain [J].
Brody, David L. ;
Magnoni, Sandra ;
Schwetye, Kate E. ;
Spinner, Michael L. ;
Esparza, Thomas J. ;
Stocchetti, Nino ;
Zipfel, Gregory J. ;
Holtzman, David M. .
SCIENCE, 2008, 321 (5893) :1221-1224
[10]  
Cirrito JR, 2003, J NEUROSCI, V23, P8844