P3-198: IS LEPTIN A CAUSE OF HIPPOCAMPAL FORMATION INSULIN RESISTANCE IN MCI AND AD?

Background: Leptin can impair signaling of the insulin receptor (IR) by promoting suppressor of cytokine signaling 1 and 3 (SOCS1 and SOCS3) binding with the IR. We studied if this is a cause of insulin resistance in the hippocampal formation (HF) of mild cognitively impaired (MCI) and Alzheimer’s disease dementia (ADd) cases represented in the ADRC brain banks of Rush University and the University of Pennsylvania. Methods: Fresh frozen HF tissue was obtained from age- and -sex matched Caucasians with no history of diabetes and low postmortem intervals (m ± SD = 6.75 ± 2.2 h). They were from non-cognitively impaired (NCI), non-amnestic MCI (naMCI), amnestic MCI (aMCI), and ADd cases (n = 10 per clinical group). Using our ex vivo stimulation protocol (Talbot and Wang et al., JCI 122: 1316-1338, 2012), the tissues were tested for signaling responses to 0, 1, or 10 nM insulin, 10 nM leptin, or 1 nM insulin after treatment with 10 nM leptin. ELISAs were used to measure leptin levels. Statistical significance was defined as p < 0.05. Results: HF responsiveness to 1 and 10 nM insulin was significantly reduced in all the clinical groups at all levels of the insulin receptor (IR) - insulin receptor substrate 1 - Akt1 pathway. Consistent with leptin-induced insulin resistance, HF leptin was significantly elevated in all the clinical groups, especially naMCI, as were baseline levels of leptin-related SOCS1 and SOCS3 bound to IRβ. However, signaling responses to 10 nM leptin were themselves significantly blunted at the level of JAK2 and STAT3 in aMCI and ADd and in all the clinical groups at the level of SOCS1 and SOCS3 bound to the IR. Moreover, 10 nM leptin treatment of the HF significantly reduced insulin responsiveness in naMCI, but not in aMCI or ADd. Conclusions: While elevated basal levels of leptin and SOCS 1 and 3 bound to IRβ suggest a role for leptin in the HF insulin resistance found in naMCI, aMCI, and AD, such a role appears diminished by simultaneous HF leptin resistance in those conditions with the notable exception of naMCI.