Insulin Signaling and Synaptic Physiology: Insights into the Pathogenesis of Alzheimer's Disease
Type of Degreedissertation
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An emerging hypothesis is that desensitization of the neuronal insulin receptor (central insulin resistance) may contribute to the pathogenesis of Alzheimer’s disease (AD). It is believed that deficits in glutamatergic function may underlie the cognitive deficits observed in AD. Therefore, understanding the impact of central insulin resistance on glutamatergic physiology may lead to therapeutic manipulations which halt the progression of AD before irreversible damage occurs. A useful model of central insulin resistance is the ic-STZ (intracerebroventricular streptozotocin) animal model. STZ is known to inhibit insulin receptor function in the brains of these animals. Moreover, these animals display classic AD-type pathology including amyloid-beta deposition, tau hyperphosphorylation, neuroinflammation and deficits in spatial memory performance. Therefore, these animals were utilized in this study to elucidate the effect of central insulin resistance on glutamatergic synaptic physiology. We performed extracellular field recordings in acute hippocampal slices from ic-STZ rats and sham infused controls and found that these animals exhibit severe deficits in basal synaptic transmission and long-term potentiation (LTP). Based on input-output relations and paired-pulse facilitation experiments, we hypothesized that these deficits in synaptic transmission arise from a disturbance of postsynaptic physiology. The AMPA-type glutamate receptor mediates the majority of basal excitatory synaptic transmission and is essential for the induction of LTP during the acquisition of new memory. Whole cell patch clamp recordings revealed a profound deficit in AMPA receptor-mediated currents, which we determined are due in part to changes in the function of the individual AMPA receptors. Protein and mRNA expression analysis from these animals suggest that these deficits may also be explained by altered AMPA receptor-subunit composition. Our results suggest that cellular trafficking of the GluR1 AMPA receptor subunit may be impaired in these brains and future investigation into the precise role of insulin in glutamate receptor trafficking seems warranted. We utilized several biochemical techniques to detect changes in GSK-3beta, Akt, integrin-linked kinase (ILK), BNDF and Erk-1/2 at the transcriptional, translational and posttranslational levels. The results of these studies suggest a novel role for ILK in synaptic plasticity and provide preliminary evidence for a role for ILK in neurodegeneration. Understanding more about this kinase and its role in neuronal function may lead to novel therapeutic targets for neurodegenerative disease and learning and memory disorders.