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Experimental Genetics Group
Am J Pathol, 2000 Nov;157(5):1495-1510. Tesseur I1, Van Dorpe J1, Bruynseels K1, Bronfman F1, Sciot R2, Van Lommel A2, Van Leuven F1. 1Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, University Hospitals Leuven, K.U.Leuven, Leuven, Belgium. 2Department of Pathology, University Hospitals Leuven, K.U.Leuven, Leuven, Belgium. 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 in 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.  FULL TEXT |
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