Impact of APOE and Sex on Vulnerable Neuron-Specific Functional Network

2018

Apolipoprotein E (APOE), the most important genetic predisposition factor for Alzheimer’s disease, seems to have direct effects on the formation of amyloid plaques but also many other plaque-independent effects on different types of brain cells, including on neurons. The precise mechanisms of these effects are not known. We have developed tools—a set of genetically engineered mice (so-called bacTRAP mice)—to make the full inventory of all proteins present in any specific type of neuron, in particular in neurons that display differential vulnerability to neurodegeneration.

In this proposal we set out to understand the effects of different alleles of APOE—the risk allele APOE4 as well as the protective allele APOE2—on the most vulnerable neurons of the brain, entorhinal cortex layer II (ECII) and hippocampal CA1 neurons. For that purpose, we first need to breed Cure Alzheimer’s humanized APOE mice with our genetically engineered bacTRAP mice for two generations. We obtained the first generation already, and are now setting up the second generation in that breeding scheme.

We will use these crossed mice to comprehensively profile ECII and CA1 neurons in the presence of the different human alleles of APOE, and in both female and male mice, since we have evidence that ECII neurons could display different profiles in males and females, because they are equipped with sensors for estrogen. More specifically, we will investigate if the human risk allele of APOE is putting ECII neurons in an increased vulnerability state compared with the neutral or the protective alleles of APOE.

2017

APOE, the most important genetic predisposition factor for sporadic Alzheimer’s disease, long has been known for its effect on the formation of amyloid plaques. There is evidence for another role of APOE on neuron function independent of amyloid beta. We have developed tools to make the full inventory of all proteins present in a specific type of neuron, in particular in neurons that display differential vulnerability to neurodegeneration. Entorhinal cortex layer II (ECII) and hippocampal CA1 neurons are both crucial for new memory formation, and are the most susceptible to degeneration. This proposal will comprehensively profile ECII and CA1 neurons in mice bred to carry the different human alleles of APOE, and investigate whether the human risk allele of APOE is putting ECII neurons in an increased vulnerability state compared with the neutral or the protective alleles of APOE. We also have evidence that ECII neurons could display different profiles in males and females, because they are equipped with sensors for estrogen. In light of the increased prevalence of AD for women, we will investigate if APOE and sex interact to alter the vulnerability of ECII neurons. Potential proteins modulated by APOE and/or sex that make ECII neurons more vulnerable could represent new drug targets to prevent ECII neurons from degenerating.