Human apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology

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Abstract

The human APOE*4 allele is associated with an early age of onset and increased risk of Alzheimer's disease (AD). Long before the onset of AD, cognitive deficits can be identified in APOE*4 carriers. We examined neurons in the lateral amygdala of young apolipoprotein (apo) E3 and apoE4 targeted replacement (TR) mice for changes in synaptic integrity. ApoE4 mice displayed significantly reduced excitatory synaptic transmission and dendritic arborization. Despite these changes there were no signs of gliosis, amyloid deposition or neurofibrillary tangles in these mice. To our knowledge, this is the first study to suggest that cognitive deficits in APOE*4 carriers are due to inherent defects in synaptic function that appear prior to any age-dependent markers of neuropathology.

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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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