Elsevier

Neuroscience

Volume 122, Issue 2, 2003, Pages 305-315
Neuroscience

Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer's disease patients

https://doi.org/10.1016/j.neuroscience.2003.08.007Get rights and content

Abstract

Dendritic spines are postsynaptic sites of excitatory input in the mammalian nervous system. Apolipoprotein (apo) E participates in the transport of plasma lipids and in the redistribution of lipids among cells. A role for apoE is implicated in regeneration of synaptic circuitry after neural injury. The apoE4 allele is a major risk factor for late-onset familial and sporadic Alzheimer's disease (AD) and is associated with a poor outcome after brain injury. ApoE isoforms are suggested to have differential effects on neuronal repair mechanisms. In vitro studies have demonstrated the neurotrophic properties of apoE3 on neurite outgrowth. We have investigated the influence of apoE genotype on neuronal cell dendritic spine density in mice and in human postmortem tissue. In order to compare the morphology of neurons developing under different apoE conditions, gene gun labeling studies of dendritic spines of dentate gyrus (DG) granule cells of the hippocampus were carried out in wild-type (WT), human apoE3, human apoE4 expressing transgenic mice and apoE knockout (KO) mice; the same dendritic spine parameters were also assessed in human postmortem DG from individuals with and without the apoE4 gene. Quantitative analysis of dendritic spine length, morphology, and number was carried out on these mice at 3 weeks, 1 and 2 years of age. Human apoE3 and WT mice had a higher density of dendritic spines than human E4 and apoE KO mice in the 1 and 2 year age groups (P<0.0001), while at 3 weeks there were no differences between the groups. These age dependent differences in the effects of apoE isoforms on neuronal integrity may relate to the increased risk of dementia in aged individuals with the apoE4 allele. Significantly in human brain, apoE4 dose correlated inversely with dendritic spine density of DG neurons cell in the hippocampus of both AD (P=0.0008) and aged normal controls (P=0.0015). Our findings provide one potential explanation for the increased cognitive decline seen in aged and AD patients expressing apoE4.

Section snippets

Animals

C57BL/6 male mice used for these experiments were wild-type (WT), and murine apoE−/− (knock-out, KO). In addition, human apoE3+/+ and apoE4+/+ on a murine apoE−/− background, were used Holtzman et al., 1999, Holtzman et al., 2000a, Sun et al., 1998. The expression level of apoE in the transgenic mouse lines, and in the WT mice was equivalent in the brain as determined by Western blot analysis, whereas immunoreactivity was not detected in apoE KO mice (Sun et al., 1998). Mice were maintained in

Total dendritic spine number per neuron in mice

Confocal microscopic imaging of gene gun labeling neurons provided excellent visualization of dendritic spines as previously reported Gan et al., 2000, Grutzendler et al., 2003; see Fig. 4). A total of 20–43 granule cells were included in the final analysis per group (five to 10 cells per animal, four to five mice per group). All of the neurons resided in the DG of the hippocampus. At 3 weeks of age no difference was evident among the four groups of mice (Fig. 1A). However, by 12 months of age

Discussion

Our studies demonstrate the importance of apoE isotype expression for age-related changes in dendritic spine density, both in animal models and in human tissue. The inheritance of the apoE4 allele is well recognized to be the major identified, genetic risk factor for the development of late-onset AD Laws et al., 2003, Wisniewski and Frangione, 1996. AD is the most common cause of dementia and is characterized by the accumulation of Aβ in the form of senile plaques and congophilic angiopathy,

Acknowledgements

This work was supported by NIH grants AG15408, AG17617 and AG13956.

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