Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology
Section snippets
Preparation of animals
The TR mice were created by gene targeting as described previously (Sullivan et al., 1997). Briefly, the construction of the TR mice differ from other apoE transgenic mice in that human APOE genomic fragments were used to replace the mouse Apoe gene via homologous recombination. All three lines of apoE TR mice contain chimeric genes consisting of mouse 5′ regulatory sequences continuous with mouse exon 1 (noncoding) followed by human exons (and introns) 2–4 (Sullivan et al., 1997). Thus, all
Absence of neuropathology in young human apoE TR mice
We examined age (7 month), sex (male), and genotype (apoE3 vs. apoE4) matched TR mice for signs of neurodegeneration. Using antibodies against common markers of neurodegeneration (i.e., glial fibrillary acidic protein for gliosis, tau for neurofibrillary tangles, and Aβ for amyloid deposits), we did not detect any differences in staining between the apoE3 and E4 mice (data not shown). ApoE immunoreactivity in the amygdala of E3 and E4 mice showed the same glial pattern of apoE expression as
Discussion
The amygdala is a limbic structure that plays a significant role in emotional learning, memory, and behavior (Fried et al., 2001, Hamann et al., 2002). Like other limbic structures, the amygdala is a plastic area of the brain and is responsible for mediating thalamic inputs from various sensory stimuli. Along with the hippocampus and entorhinal cortex, it is one of the first structures to show atrophy and histopathological changes characteristic of AD (Braak et al., 1993). Our studies show
Acknowledgments
We wish to thank Jason Moss for expert technical assistance. We thank Drs. Warren Strittmatter and Jim Burke for critical review of the manuscript. This work was supported by an NIA grant P50 AG05128-18, and grants from the Department of Veterans Affairs to SDM and WAW.
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