Alzheimer's disease (AD), unlike the other leading causes of death, does not have a cure or an effective intervention strategy. The largest genetic risk factor for AD is APOE, with the ϵ4 allele increasing and the ϵ2 allele decreasing one's risk for the disease. It remains unclear how ApoE isoforms contribute to various AD-related pathological changes (e.g. amyloid plaques, synaptic and neuron loss). Here, we characterize the differences between the at risk group for AD (the ϵ4 carriers) and the not-at risk group (non-ϵ4 carriers), to determine what underlies APOE-related risk to AD.
To do this, we utilized APOE Targeted Replacement (TR) mice. These animals express the human APOE alleles (APOE-ϵ2, APOE-ϵ3, or APOE-ϵ4) under the mouse APOE promoter, and do not develop the plaques and tangles diagnostic of AD. We found that despite the lack of AD pathology, APOE-ϵ4 TR mice had alterations at the synapse. Specifically, APOE-ϵ4 TR mice have fewer dendritic spines at the post-synaptic terminal and simpler neuronal morphology compared to the other APOE genotypes. Pre-synaptically, we found that APOE-ϵ4 TR mice have reduced levels of glutaminase, increased levels of VGLUT1 and increased levels of glutamine (GLN). Taken together, these data suggest that the APOE-ϵ4 allele affects brain function well before AD pathogenesis occurs.
To begin addressing the mechanism by which APOE can impact dendritic spine morphology, we examined the role of the apoE receptor, ApoEr2. We found that increased surface levels of ApoEr2 promoted dendritic spine formation and that the ligand binding domain is necessary for us to observe these effects, suggesting that ApoEr2 may be involved in APOE related changes at the synapse.
To test whether there are CSF biomarkers of APOE-associated risk that could be followed in preventative therapeutic AD approaches, we examined levels of GLN in ante-mortem CSF samples from healthy controls. Consistent with our mouse studies, we found that APOE-ϵ4 carriers had higher levels of GLN compared to the other genotypes. These studies suggest that GLN may be a novel biomarker used to assess AD patients in their pre-clinical phases and as a therapeutic measure in preventative AD trials.
|Advisor:||Rebeck, G. William|
|Commitee:||Bayer, Barbara, Cookson, Mark R., Maguire-Zeiss, Kathleen, Turner, R. Scott|
|School Location:||United States -- District of Columbia|
|Source:||DAI-B 74/08(E), Dissertation Abstracts International|
|Keywords:||Alzheimer's disease, Apoe, Biomarkers, Synapse|
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