P2‐222: Changes in the expression of somatostatin 3 receptor (SSTR3) and p75NTR in the hippocampal primary cilia of Alzheimer's disease transgenic mice

Background: APOE e4 is the strongest genetic risk factor for late-onset, sporadic Alzheimer’s disease, strongly increasing risk and decreasing age of onset, whereas the APOE e2 allele decreases risk. Convincing evidence has revealed accelerated onset of amyloid deposition in APOE e4-carriers, leading to the hypothesis that APOE genotype differentially regulates AD risk and onset via effects on As accumulation. Using PDAPP/human apoE targeted replacement (PDAPP/TRE) mice that exhibit apoE isoform-dependent levels of As burden (E4 > E3 > E2), we have found that human apoE isoforms differentially modulate endogenous As clearance, but not synthesis, in a manner that corresponds to the apoE isoform-dependent pattern of As accumulation in older mice. Here, we sought to assess the contribution of both the concentration and isoform of apoE in the regulation of ISF As clearance by acute infusion of synthetic human apoE particles during in vivo microdialysis. Methods: Synthetic particles containing apoE2, apoE3, and apoE4 were prepared, verifying functionality in vitro using cholesterol efflux assays. We next bred PDAPP/E2, PDAPP/E3, and PDAPP/E4 mice and aged them to 3 months of age for in vivo microdialysis experiments. To acutely assess the effect of each apoE isoform, apoE particles were directly infused around the implanted 38kDa microdialysis probe during simultaneous sampling of the brain interstitial fluid of freely behaving mice. To assess the effect of each apoE infusion on As clearance, each mouse was then given an intraperitoneal injection of a potent gamma secretase inhibitor in order to halt As production, allowing for the determination of As half-life after measurement with a sandwich ELISA. Results:We report that synthetically prepared apoE particles composed of phospholipids, cholesterol, and human apoE are functional and can be utilized to assess acute effects of human apoE on As metabolism in vivo. Specifically, in PDAPP/TRE mice, we report that acute infusions of synthetic human apoE particles increase ISFAs levels and decrease As clearance in a manner that depends on the isoform of apoE infused. Conclusions: These results have important implications for understanding how both the concentration and isoform of apoE influence As clearance and may be informative in designing therapeutic strategies that target apoE.