Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human Apolipoprotein E4 transgenic mice

doi:10.1016/S0306-4522(00)00065-8

Neuroscience

Volume 97, Issue 4, May 2000, Pages 685-692

https://doi.org/10.1016/S0306-4522(00)00065-8 Get rights and content

Abstract

To investigate the relationship between the three isoforms of apolipoprotein E (E2, E3 and E4) and the integrity of the synaptic circuitry in the dentate gyrus of the hippocampus, we have estimated the synapse per neuron ratio and mean apposition zone area per synapse at the electron microscope level in the dentate gyrus of apolipoprotein E knockout and human apolipoprotein E transgenic mice aged six to 24 months. During ageing, only in human apolipoprotein E4 mice was there a decrease in synapse per neuron ratio, accompanied by an increase in synaptic size. When these mice were compared with human apolipoprotein E2, apolipoprotein E knockout and wild-type mice at old age, they displayed the lowest synapse per neuron ratio, but similar apposition zone area. In contrast, as in our previous study, aged apolipoprotein E knockout mice did not show any sign of synaptic degeneration.

The functional consequences of such morphological changes remain to be determined. However, if such age-related loss of synapses occurred in the brain of Alzheimer apolipoprotein E4 patients, they might be additive to pathological processes and could contribute to greater cognitive impairment.

Section snippets

Transgenic mice

ApoE transgenic mice were derived from colonies produced at Duke University Medical Center (Durham, NC, U.S.A.). WT mice were C57BL/6J. ApoE KO mice were obtained from a colony produced by Dr Maeda (UNC, Chapel Hill, NC, U.S.A.), and generated from C57BL/6J blastocysts and 129J modified embryonic stem cells.⁵⁵ They were back-crossed at least six times to C57BL/6J animals.

Heterozygous hApoE transgenic mice were generated by Dr Xu (DUMC, Durham, NC, U.S.A.), as described in detail in Xu et al.⁸¹

Qualitative comparison of synaptic and neuronal morphometry in the dentate gyrus of apolipoprotein E transgenic mice

Examination of photomicrographs (Fig. 1A–D) taken in the MML of the DG showed that there were no synaptic alterations, similar to those described in the brain of AD patients, in any group of mice at any age. The synaptic terminals were generally full of numerous round and regular synaptic vesicles accompanied occasionally by normal mitochondria. There was neither enlargement of the terminals nor the presence of multilamellar or electron-dense bodies. Microtubules in the dendrites were regularly

Discussion

The data presented here show that the pattern of age-dependent synaptic changes in the DG of ApoE transgenic mice varies with the ApoE genotype. In agreement with a preliminary study³ in our laboratory, aged ApoE KO mice did not show any sign of synaptic degeneration. In contrast, hApoE4 mice showed a significant ageing-associated decline in the synapse per neuron ratio accompanied by an increased synaptic size, when compared with hApoE2, WT and ApoE KO mice.

Conclusions

The present study utilizing human ApoE and ApoE KO transgenic mice showed that, during ageing, only in hApoE4 mice is there alteration in synaptic parameters, a decrease in the synapse per neuron ratio, accompanied by an increase in synaptic size in the DG. Moreover, when these mice were compared with other genotypes at old age, they displayed the lowest synapse per neuron ratio. Our results agree well with other studies, which relate possession of the ε4 allele with poor ability of ApoE4 for