Date of Award


Degree Name

Doctor of Philosophy


Molecular, Cellular, and Systemic Physiology

First Advisor

Patrylo, Peter


Recent epidemiological data have shown that metabolic disease is known to increase the propensity for developing cognitive decline and dementia, particularly Alzheimer’s disease (AD). While this interaction is not completely understood, clinical studies suggest that both hyper- and hypoinsulinemia are associated with an increased risk for developing AD. Indeed, insulin signaling is altered in post-mortem brain tissue from AD patients and insulin and treatments known to enhance insulin signaling, can improve cognitive function. Furthermore, clinical evidence has shown that AD patients and mouse models of AD often display alterations in peripheral metabolism. Since insulin is primarily derived from the periphery it is likely that peripheral alterations can lead to alterations in central nervous system (CNS) insulin signaling and that these changes contribute to cognitive decline. Recent results from our laboratory have shown that in both the APP/PS1 and 3xTg-AD mouse models of AD, peripheral metabolic alterations exist at an early age. Specifically, 3xTg-AD mice demonstrate impaired glucose tolerance at 1 month of age associated with a decrease in insulin and insulin secretion in response to a glucose challenge. This led to the hypothesis that insulin signaling in the CNS would be decreased as a result of decreased peripheral insulin and insulin transport into the CNS. Indeed, insulin signaling through the PI3K/AKT signaling pathway, but not the MAPK/ERK pathway, was decreased in the hippocampus of old, but not young, 3xTg-AD mice. PI3K/AKT signaling can affect several downstream molecules including glycogen synthase kinase 3 (GSK3), glucose transporters (GLUTs), and ATP dependent potassium (KATP) channels. We first examined GSK3 and pTau and found that both GSK3β and pTau were increased in aged 3xTg-AD mice. Next we looked at the translocation of GLUT3 and GLUT4 since both are found in the hippocampus and have recently been shown to be insulin sensitive. Our results showed that GLUT3 translocation, but not GLUT4, was decreased in the hippocampus of aged 3xTg-AD mice. Finally, since KATP channels are found in intracellular organelles as well as in the plasma membrane we examined crude plasma membrane and total fractions of KATP channel subunits Kir6.1 and Kir6.2 and found that the plasma membrane fraction of Kir6.2 was significantly increased. To assess how these changes corresponded with the time course of pathology and cognitive deficits we additionally looked at these changes in 6-8 month and 14-16 month animals. Interestingly, though peripheral insulin was decreased early on, changes in CNS PI3K/AKT insulin signaling did not occur until 18-20 months of age. Changes in GSK3β (but not pTau) and GLUT3 were consistent with this time point suggesting that they were potentially due to the decrease in PI3K/AKT signaling. Since these changes were not consistent with a decrease in peripheral insulin levels it suggests that another factor must be at play. One such factor is inflammation. The AD brain is characterized by inflammation and inflammatory compounds are known to block insulin signaling. KATP channels are not only insulin sensitive but have been shown to play a role in cognition, AD and epilepsy. Thus, to follow up the studies on KATP channels we used immunohistochemistry (IHC), to examine regional and cell specific changes. To our surprise we found that Kir6.2, a subunit typically found primarily in neurons, was present in reactive astrocytes. This finding was further examined in human AD tissue and a similar change was seen. Astrocytes become reactive during damage or under inflammatory conditions, such as AD, diabetes, traumatic brain injury (TBI), epilepsy and in normal aging. When they become reactive both gene expression and functions can change. Since reactive astrocytes and inflammation are a common finding among many neuropathological changes we looked at another neuropathological condition with several similarities to AD, epilepsy. These studies revealed that epileptic mice displayed a similar change in Kir6.2 in reactive astrocytes. Since both conditions are characterized by inflammation we next hypothesized that chronic peripheral inflammation induced by LPS would be enough to drive this change. These studies revealed that while 1 day of LPS treatment was not enough to induce a change in astrogliosis and Kir6.2 expression, three days caused a significant increase in Kir6.2 in reactive astrocytes. This suggests that an increase in Kir6.2 in reactive astrocytes could contribute to the difference in function in these cells and subsequently contribute to altered function in neuropathological disease. Taken together, these studies demonstrate an intricate balance between metabolism and inflammation in the CNS and further suggest that metabolic alterations could be a common link in neuropathological diseases that share similar phenotypic changes, as occurs in AD and epilepsy (i.e. cognitive decline, enhanced seizure susceptibility). Developing a better understanding of metabolism, inflammation, and cortical function/dysfunction could potentially lead to the identification of better treatment options for several neuropathological conditions including AD.




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