Mechanisms by which incretin receptor agonists reduce hippocampal insulin
resistance in mild cognitive impairment and Alzheimer???s dementia 
   Lead Investigator:    Konrad Talbot
   Institution      :    Loma Linda University School of Medicine
   E-Mail           :    ktalbot@llu.edu
   Proposal ID      :    1640



   Proposal Description:
   Work on our NIA grant (R01 AG057658) using an ex vivo insulin stimulation protocol showed that the hippocampal formation is profoundly insulin resistant not only in Alzheimer?#128#153s disease dementia (ADd), but also in amnestic and non-amnestic mild cognitive impairment (MCI). In addition, the work showed that such insulin resistance can be significantly reduced in all such cases by brief hippocampal exposure to agonists of the incretin receptors for glucagon-like peptide-1 (GLP-1) and/or for glucose-dependent insulinotropic polypeptide (GIP), including incretin receptor agonists (IRAs) that are FDA-approved for treatment of type 2 diabetes. In non-amnestic MCI cases, IRAs virtually restore hippocampal insulin responsiveness. IRAs appear to reduce hippocampal insulin resistance via multiple mechanisms, because our work indicates that the proximal causes of such resistance are different in amnestic and non-amnestic MCI (see below). To continue this work, we need additional hippocampal tissue from MCI and ADd cases to identify what those different mechanisms are in order to understand the range of benefits and possible adverse effects of IRAs in AD treatment. This is especially important, because our validated ex vivo stimulation method (Talbot et al., Journal of Clinical Investigation 122: 1316-1338, 2012) allows us to obtain signaling data from actual MCI and ADd cases within 14 hours of death and thereby directly test signaling responses of potentially therapeutic drugs on such cases.      There are two specific aims of the study for which we are requesting fresh frozen hippocampal tissue. One is to test the generalizability of our previous finding that serine phosphorylation of insulin receptor substrate-1 (IRS-1) drives hippocampal insulin resistance in amnestic MCI and ADd cases, but not in non-amnestic MCI, which we found to be biochemically distinct from amnestic MCI. The second aim is to test the hypothesis that a downstream abnormality in leptin signaling