ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory

被引:120
作者
Levi, O
Jongen-Relo, AL
Feldon, J
Roses, AD
Michaelson, DM [1 ]
机构
[1] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiochem, IL-69978 Ramat Aviv, Israel
[2] Swiss Fed Inst Technol, Dept Biol, Lab Behav Neurobiol, Zurich, Switzerland
[3] Duke Univ, Dept Neurol, Durham, NC USA
关键词
Alzheimer's disease; apolipoprotein E; enriched environment; learning; synaptogenesis; synaptophysin; transgenic mice; working memory;
D O I
10.1016/S0969-9961(03)00045-7
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype. (C) 2003 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:273 / 282
页数:10
相关论文
共 45 条
[1]  
ANGER WK, 1991, NEUROTOXICOLOGY, V12, P403
[2]  
Arendt T, 1997, J NEUROSCI, V17, P516
[3]   Dominant negative effects of apolipoprotein E4 revealed in transgenic models of neurodegenerative disease [J].
Buttini, M ;
Akeefe, H ;
Lin, C ;
Mahley, RW ;
Pitas, RE ;
Wyss-Coray, T ;
Mucke, L .
NEUROSCIENCE, 2000, 97 (02) :207-210
[4]   The effects of APOE genotype on age at onset and progression of neurodegenerative diseases [J].
Chapman, J ;
Korczyn, AD ;
Karussis, DM ;
Michaelson, DM .
NEUROLOGY, 2001, 57 (08) :1482-1485
[5]   A simple and efficient method for apolipoprotein E genotype determination [J].
Chapman, J ;
Estupinan, J ;
Asherov, A ;
Goldfarb, LG .
NEUROLOGY, 1996, 46 (05) :1484-1485
[6]   Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury [J].
Chen, Y ;
Lomnitski, L ;
Michaelson, DM ;
Shohami, E .
NEUROSCIENCE, 1997, 80 (04) :1255-1262
[7]   GENE DOSE OF APOLIPOPROTEIN-E TYPE-4 ALLELE AND THE RISK OF ALZHEIMERS-DISEASE IN LATE-ONSET FAMILIES [J].
CORDER, EH ;
SAUNDERS, AM ;
STRITTMATTER, WJ ;
SCHMECHEL, DE ;
GASKELL, PC ;
SMALL, GW ;
ROSES, AD ;
HAINES, JL ;
PERICAKVANCE, MA .
SCIENCE, 1993, 261 (5123) :921-923
[8]   INCREASES IN CORTICAL DEPTH AND GLIA NUMBERS IN RATS SUBJECTED TO ENRICHED ENVIRONMENT [J].
DIAMOND, MC ;
LAW, F ;
RHODES, H ;
LINDNER, B ;
ROSENZWEIG, MR ;
KRECH, D ;
BENNETT, EL .
JOURNAL OF COMPARATIVE NEUROLOGY, 1966, 128 (01) :117-+
[9]  
Fagan AM, 2000, MICROSC RES TECHNIQ, V50, P297, DOI 10.1002/1097-0029(20000815)50:4<297::AID-JEMT9>3.0.CO
[10]  
2-C