TY - JOUR
T1 - Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord
AU - Tesseur, Ina
AU - Van Dorpe, Jo
AU - Bruynseels, Koen
AU - Bronfman, Francisca
AU - Sciot, Raf
AU - Van Lommel, Alfons
AU - Van Leuven, Fred
N1 - Funding Information:
Supported by the ‘Fonds voor Wetenschappelijk Onderzoek’ (FWO-Vlaanderen), the Interuniversity-Network for Fundamental Research (IUAP), by the special Action Program for Biotechnology of the Flemish government (VLAB/IWT, COT-008), by the Rooms-fund, by Janssen Research Foundation, and by K. U. Leuven Research and Development.
PY - 2000/1/1
Y1 - 2000/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0033694470&partnerID=8YFLogxK
U2 - 10.1016/S0002-9440(10)64788-8
DO - 10.1016/S0002-9440(10)64788-8
M3 - Article
AN - SCOPUS:0033694470
SN - 0002-9440
VL - 157
SP - 1495
EP - 1510
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -