Evaluation of the neuroimmune mechanisms influencing therapeutic targetingpotential of the LH/CG receptor in the menopausal and AD brain - PROJECT SUMMARY Menopause is midlife event that promotes adverse outcomes in the female brain. The systemic proinflammatory state induced by large fluctuations and changes in ovarian and pituitary hormones is thought to exacerbate peripheral and centrally mediated neuroinflammation that increase the risk of AD in women compared to men. Our previous work has demonstrated that the gonadotropin LH/CG receptor-ligand complex is as a therapeutically relevant nexus for menopausal and AD-related cognitive and neuroplasticity loss. We have now identified that these benefits may be facilitated through immune regulating properties; known for this receptor complex in the periphery but completely unexplored in the CNS. We have identified that LH/CG receptor activation using hCG is particularly effective at normalizing myeloid cell peripheral infiltration exacerbated by ovariectomy (to model menopause) in the rodent AD model brain. This proinflammatory mechanism is regarded as a key driver of AD pathogenesis, underscoring the significance of evaluating this hormone-receptor complex in this context. A potential immune-regulating role for the LHCGR in the CNS are bolstered by its expression in microglia and excitatory neurons, both key mediators of neuroinflammation in disease states. Therefore, here we seek to address if this hormone-receptor complex yields CNS benefits through regulation of neuroinflammatory mechanisms that are relevant in AD development. Specifically, AIM 1 will evaluate the cell specific role of the LHCGR signaling on CNS function, neuroplasticity, and inflammatory processes through conditional deletion. AIM 2 will address whether the functional and neuroplasticity benefits associated with stimulating this receptor complex involve the inhibition of peripheral infiltration mechanisms; also, how this proinflammatory mechanism and therapeutic benefits are impacted by age, reproductive status, and amyloidosis. AIM 3 will determine how age and reproductive status specific baseline levels of centrally produced ligand (LH), receptor expression levels, and/or its cellular localization influence the therapeutic outcomes of this receptor’s target engagement. This work will advance our understanding of this understudied receptor complex in the brain and its relation to incrased risk of AD development in women. More broadly, it will expand our knowledge base on neuroendocrine regulation of important disease driving neuroinflammatory processes. Notably, given the involvement of peripheral immune cell infiltration-based inflammatory processes, in several neurological conditions (TBI, neurogenerative disorders, stroke, epilepsy, severe infection) the mechanistic evaluation of LHCGR signaling in this context can inform therapy beyond AD risk factors.
