Sex and genotype influence neural stem cells in a model of sporadic Alzheimer’s disease

The greatest non-modifiable risk factors for Alzheimer’s disease (AD) are advancing age, female sex, and at least one APOEε4 allele. Females with at least one APOEε4 allele are at the highest risk for earlier AD onset, greater neuropathology, and steeper cognitive decline. Neurogenesis in the hippocampus is altered in AD, and sex differences have been identified, but studies on the effect of sex and APOE genotype on neurogenesis are limited. The present study aimed to identify sex and genotype differences in neural stem cells and neurogenesis in adult (7-month-old) transgenic mice expressing human (h)APOEε3 or (h)APOEε4 alleles. Newly formed cells were labelled using the thymidine analogue BrdU, and observed at timepoints ranging from 2 hours, 24 hours, 2 weeks and 4 weeks allowing a window into the dynamics of neurogenesis. We investigated the identity of these new cells using the marker Sox2 to identify pluripotent neural stem cells, and NeuN to classify mature neurons. We found that female hAPOEε4 mice had a higher density of Sox2-ir cells compared to hAPOEε3 females in the ventral hippocampus, and this effect was reversed in males as hAPOEε4 had a lower density of Sox2-ir cells than hAPOEε3. Furthermore, the percentage of BrdU/Sox2-ir cells declined over time but increased at the 4 week timepoint to levels comparable to the 2 hour timepoint in all groups aside from hAPOEε4 females. Instead, hAPOEε4 females exhibited high BrdU/Sox2 colabelling at 2 hours and steadily declined over time. These findings indicate that females may have earlier and faster rates of neural stem cell turnover than other groups, which should be further investigated as hAPOEε4 females are a high-risk group for AD. Neuronal maturation was also affected by sex and genotype as hAPOEε3 males had the lowest overall percent of BrdU-ir cells also expressing NeuN of all the groups. Furthermore, we observed significantly greater BrdU-ir density in the dorsal compared to the ventral hippocampus, and the functional implications of this difference warrant further investigation. These findings indicate that sex and genotype differences in neural stem cells and neurogenesis in the hippocampus should be further investigated in models of AD.Medicine, Faculty ofGraduat