The Medial Septum Is Insulin Resistant in the AD Presymptomatic Phase: Rescue by Nerve Growth Factor-Driven IRS1 Activation

Basal forebrain cholinergic neurons (BFCN) are key modulators of learning and memory and therefore are high energy-demanding neurons. Impaired neuronal metabolic process and reduced insulin signaling, referred to as insulin resistance, continues to be reported in early phase of Alzheimer’s (AD), that has been recommended to become “Type 3 Diabetes.” We hypothesized that BFCN may develop insulin resistance as well as their consequent failure represents among the earliest event in AD. We discovered that an ailment similar to insulin resistance happens in the medial septum of three several weeks old 3×Tg-AD rodents, reported to build up typical AD histopathology and cognitive deficits in their adult years. Further, we acquired insulin resistant BFCN by culturing all of them with high insulin concentrations. By way of these paradigms, we observed that nerve growth factor (NGF) reduces insulin resistance in vitro as well as in vivo. NGF activates the insulin receptor substrate 1 (IRS1) and rescues c-Fos expression and glucose metabolic process. This effect involves binding of activated IRS1 towards the NGF receptor TrkA, and it is lost in existence of the particular IRS inhibitor NT157. Overall, our findings indicate that, inside a well-established animal type of AD, the medial septum develops insulin resistance several several weeks prior to it being detectable within the neocortex and hippocampus. Remarkably, NGF counteracts molecular alterations downstream of insulin-resistant receptor and it is nasal administration restores insulin signaling in 3×Tg-AD rodents by TrkA/IRS1 activation. The mix-talk between NGF and insulin pathways downstream the insulin receptor suggests novel potential therapeutic targets to slow cognitive loss of AD and diabetes-related brain insulin resistance.