219-OR: Loss of Insulin Signaling in Microglia Impairs Cellular Uptake of Aß and Neuroinflammatory Response Exacerbating Alzheimer-Like Neuropathology

Insulin receptors are present on cells throughout the body. Dysregulation of insulin signaling in the brain has been implicated in mood, cognitive disorders, and pathogenesis of Alzheimer’s disease (AD). However, the brain is composed of multiple cells types, and little is known as to how brain insulin resistance in particular in different brain cell types contributes to the comorbidity of type 2 diabetes (T2D) and AD. In this regard, microglia are particularly interesting, since microglia are involved in the uptake and clearance of amyloid-β (Aβ) and formation of neuroinflammation. To investigate the role of insulin signaling in microglial function and development of AD, we have created an inducible microglia-specific insulin receptor knockout (MG-IRKO) and found that loss of microglial insulin signaling in these mice results in alterations in mood, social behavior and impairment in systemic metabolism. At a molecular level, utilizing RiboTag to isolate and profile microglial-specific ribosome-bounded mRNA, we found that loss of insulin receptor resulted in alterations in pathways associated with innate immunity and cellular metabolism in microglia. In vitro, loss of insulin signaling in microglial resulted in metabolic reprograming with a switch to more glycolytic metabolism, and this was associated with impaired ability of microglia in Aβ uptake. When the MG-IRKO mice were crossed with an AD mouse model (5xFAD mice) to create MG^IRKO/5xFAD mice, the resultant mice exhibit increased levels of Aβ plaque formation and elevated neuroinflammation marked by increased IFN-γ. Thus, insulin signaling in microglia plays a key role in microglial cellular metabolism, neuroinflammation and the ability of the cells to uptake Aβ, such that loss of insulin signaling in microglia accelerates AD pathogenesis. Together, these data indicate the potential importance of targeting insulin signaling in microglia in treatment of AD.