Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord

被引:115
作者
Tesseur, I
Van Dorpe, J
Bruynseels, K
Bronfman, F
Sciot, R
Van Lommel, A
Van Leuven, F
机构
[1] Katholieke Univ Leuven VIB, Expt Genet Grp, Ctr Human Genet, Univ Hosp Leuven, B-3000 Louvain, Belgium
[2] Katholieke Univ Leuven, Univ Hosp Leuven, Dept Pathol, B-3000 Louvain, Belgium
关键词
D O I
10.1016/S0002-9440(10)64788-8
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
The epsilon 4 allele of the human apolipoprotein E gene (ApoE4) constitutes an important genetic risk factor for Alzheimer's disease. Recent experimental evidence suggests that human ApoE is expressed in neurons, in addition to being synthesized In glial cells. Moreover, brain regions In which neurons express ApoE seem to be most vulnerable to neurofibrillary pathology, The hypothesis that the expression pattern of human ApoE might be Important for the pathogenesis of Alzheimer's disease was tested by generating transgenic mice that express human ApoE4 in neurons or in astrocytes of the central nervous system. Transgenic mice expressing human ApoE4 ill neurons developed axonal degeneration and gliosis in brain and in spinal cord, resulting in reduced sensorimotor capacities. In these mice, axonal dilatations with accumulation of synaptophysin, neurofilaments, mitochondria, and vesicles were documented, suggesting impairment of axonal transport. In contrast, transgenic mice expressing human ApoE4 in astrocytes remained normal throughout life. These results suggest that expression of human ApoE in neurons of the central nervous system could contribute to impaired axonal transport and axonal degeneration, The possible contribution of hyperphosphorylation of protein Tau to the resulting phenotype is discussed.
引用
收藏
页码:1495 / 1510
页数:16
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