Evaluating the Role of APOE Genotype in Modulating Hippocampal Angiotensin Type 1 Receptor Activity

With an aging population, AD is rapidly becoming a severe public health concern effecting roughly 1 in 9 adults age 65 and older. The development of novel approaches to prevent, slow, or treat AD is imperative and the primary focus of AD research. However, therapeutics targeting traditional pathways such as A have produced mixed, often negative, results. Therefore, the identification of novel pathways contributing to AD development and progression is key for the advancement of the field. One such pathway is the brain angiotensin system, in particular the Angiotensin II Type 1 (AT1) receptor. AT1 receptor activation in the brain is associated with many factors that both directly and indirectly lead to neuron dysfunction, many of which are also linked to APOE4, the greatest genetic risk factor for AD. Therefore, the goal of this thesis was to address the interaction of APOE genotype and the brain angiotensin II/AT1 receptor axis on neuron function and behavior in an AD-relevant context. Initially, we treated mice that express human APOE4 and human amyloid- (E4FAD) with the Angiotensin Receptor Blocker (ARB) Candesartan, which selectively inhibits the AT1 receptor. Compared to vehicle, candesartan treatment resulted in greater memory-relevant behavior and higher hippocampal presynaptic protein levels in female, but not male, E4FAD mice. The beneficial effects of candesartan in female E4FAD mice occurred in tandem with lower GFAP and Iba1 levels in the hippocampus, whereas there were no effects on markers of cerebrovascular function and Aβ levels. These results indicated that the AT1 receptor in the hippocampus may be modulating neuron function directly in the context of APOE4. To test this, we evaluated the effect of exogenous angiotensin II on the electrophysiological properties of hippocampal neurons in mice that express human APOE3 (E3FAD) or APOE4 (E4FAD) and overproduce Aβ. We established that APOE genotype independently modulates hippocampal neuron function and that while AT1 receptor activation did not impact basal synaptic transmission or synaptic facilitation, it did have a strong inhibitory effect on LTP. In summary, we demonstrated that with APOE4, activation of the AT1 receptor interferes with synaptic processes that underly learning and memory either directly, or indirectly by contributing to the APOE4-associated neuroinflammatory phenotype. These findings illuminate the brain angiotensin system as a potential pathway by which APOE4 induces cellular and behavioral deficits that contribute to AD risk and development.