Abstract
Apolipoprotein E4 (apoE4) allele is the major genetic risk factor for sporadic Alzheimer disease (AD) due to the higher prevalence and earlier onset of AD in apoE4 carriers. Accumulating data suggest that the interaction between the N- and the C-terminal domains in the protein may be the main pathologic feature of apoE4. To test this hypothesis, we used Arg-61 mice, a model of apoE4 domain interaction, by introducing the domain interaction feature of human apoE4 into native mouse apoE. We carried out hippocampus-dependent learning and memory tests and related cellular and molecular assays on 12- and 3-month-old Arg-61 and age-matched background C57BL/6J mice. Learning and memory task performance were impaired in Arg-61 mice at both old and young ages compared with C57BL/6J mice. Surprisingly, young Arg-61 mice had more mitotic doublecortin-positive cells in the subgranular zone; mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB were also higher in 3-month-old Arg-61 hippocampus compared with C57BL/6J mice. These early-age neurotrophic and neurogenic (proliferative) effects in the Arg-61 mouse may be an inadequate compensatory but eventually detrimental attempt by the system to "repair" itself. This is supported by the higher cleaved caspase-3 levels in the young animals that not only persisted, but increased in old age, and the lower levels of doublecortin at old age in the hippocampus of Arg-61 mice. These results are consistent with human apoE4-dependent cognitive and neuro-pathologic changes, supporting the principal role of domain interaction in the pathologic effect of apoE4. Domain interaction is, therefore, a viable therapeutic/prophylactic target for cognitive impairment and AD in apoE4 subjects.
Highlights
Introduction of human apolipoproteinE4 “domain interaction” into mouse apolipoprotein E
Impaired Spatial Recognition Memory and Cognitive Flexibility in 12-Month-old Arg-61 Mice—It has been reported that domain interaction in Apolipoprotein E4 (apoE4) has an effect on spatial memory [18] using the Morris water maze method
Arg-61 mice spent significantly more time on the average to find the target (26.0 Ϯ 2.9 versus 18.7 Ϯ 1.8 s; p ϭ 0.0315), they seemed to show signs of learning the new location as their time-to-target decreased with training. These data suggest that domain interaction in the mouse Apolipoprotein E (apoE) protein is able to cause impairment in certain domains of spatial learning and memory as assessed by the Radial-arm Water Maze (RAWM) reversal learning task
Summary
Introduction of human apolipoproteinE4 “domain interaction” into mouse apolipoprotein E. (2004) Neuron-specific apolipoprotein E4 proteolysis is associated with increased Tau phosphorylation in brains of transgenic mice. Young Arg-61 mice had more mitotic doublecortin-positive cells in the subgranular zone; mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB were higher in 3-month-old Arg-61 hippocampus compared with C57BL/6J mice These early-age neurotrophic and neurogenic (proliferative) effects in the Arg-61 mouse may be an inadequate compensatory but eventually detrimental attempt by the system to “repair” itself. This is supported by the higher cleaved caspase-3 levels in the young animals that persisted, but increased in old age, and the lower levels of doublecortin at old age in the hippocampus of Arg-61 mice These results are consistent with human apoE4-dependent cognitive and neuro-pathologic changes, supporting the principal role of domain interaction in the pathologic effect of apoE4. A viable therapeutic/prophylactic target for cognitive impairment and AD in apoE4 subjects
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