How does reproductive aging (menopause) influence cognitive dysfunction and AD development?
Understanding the role of Luteinizing hormone in CNS function and AD
Reproductive hormones are known to be critical modulators of cognition and neuronal function and their deregulation, particularly in women, has a clear impact on neuronal plasticity, cognition, and AD development. Estrogen (E2) has been the focus of hormone-based therapies for cognition and AD. However, our laboratory has identified and highlighted a novel role for centrally produced luteinizing hormone in CNS function. The goal of our currently funded project is to determine the involvement of the LH system on spatial memory, structural plasticity (spine morphology) and whether dysregulation of LHR signaling drives AD development. We address these questions using CRISPR/Cas9 AAV mediated knockout of brain LH and LHR in wild-type and AD mouse models.
How does metabolic disease influence neuronal metabolic dysfunction and AD pathogenesis?
Understanding the role of amylin in neuroprotection & AD pathogenesis
Epidemiologic studies have linked metabolic changes and diseases including obesity, insulin resistance, and diabetes with Alzheimer's disease, and increasing therapeutic emphasis is being placed on metabolic hormones to combat the pathogenic aspects of this disease. Our laboratory has identified that amylin, a pancreatic hormone critical in the regulation of insulin sensitivity and glucose homeostasis in the periphery, affords neuronal and functional protection in aging and AD mouse models. However, the mechanisms underlying the benefits of amylin remain unknown. To address these questions we are currently funded to dissect potential central and peripheral roles of this hormone on neuroprotection in the presence and absence of metabolic stress. We also aim to identify the specific amylin receptor complex involved in such benefits. These goals are carried out using pharmacological and genetic approaches in vivo and in vitro.
In a second funded proposal we use RNAseq, bioinformatics, and large-scale statistical analysis tools to identify hippocampal transcriptomic changes associated with the progression of metabolic disease. We are trying to identify associations between these transcript level changes and AD-specific and metabolic variables to discover the earliest signatures for AD development in both males and females.