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

Valentina Sposato,Viviana Triaca,Giulia Bolasco,Elena Fico,Matteo Spinelli,Nadia Canu,Pietro Calissano,Delio Mercanti,Maria Teresa Ciotti,Salvatore Fusco,Claudio Grassi

doi:10.1007/s12035-018-1038-4

Abstract

Basal forebrain cholinergic neurons (BFCN) are key modulators of learning and memory and are high energy-demanding neurons. Impaired neuronal metabolism and reduced insulin signaling, known as insulin resistance, has been reported in the early phase of Alzheimer’s disease (AD), which has been suggested to be “Type 3 Diabetes.” We hypothesized that BFCN may develop insulin resistance and their consequent failure represents one of the earliest event in AD. We found that a condition reminiscent of insulin resistance occurs in the medial septum of 3 months old 3×Tg-AD mice, reported to develop typical AD histopathology and cognitive deficits in adulthood. Further, we obtained insulin resistant BFCN by culturing them with high insulin concentrations. By means of these paradigms, we observed that nerve growth factor (NGF) reduces insulin resistance in vitro and in vivo. NGF activates the insulin receptor substrate 1 (IRS1) and rescues c-Fos expression and glucose metabolism. This effect involves binding of activated IRS1 to the NGF receptor TrkA, and is lost in presence of the specific IRS inhibitor NT157. Overall, our findings indicate that, in a well-established animal model of AD, the medial septum develops insulin resistance several months before it is detectable in the neocortex and hippocampus. Remarkably, NGF counteracts molecular alterations downstream of insulin-resistant receptor and its nasal administration restores insulin signaling in 3×Tg-AD mice by TrkA/IRS1 activation. The cross-talk between NGF and insulin pathways downstream the insulin receptor suggests novel potential therapeutic targets to slow cognitive decline in AD and diabetes-related brain insulin resistance.

Highlights

The basal forebrain cholinergic system (BFCS) modulates many important behaviors, through robust inputs to the cortex and hippocampus [1, 2] and reciprocal feedback projections [3]
The phosphorylated and total levels of Insulin receptors (IR), insulin receptor substrate 1 (IRS1), and AKT were measured after insulin administration
We found that the levels of pIRY1150/1151 (274.7 ± 56.5% of CTR; *p < 0.05; Fig. 2c), pIRS1Y608 (207.1 ± 18.1% of CTR; *p < 0.05; Fig. 2d) and pAKT (248.9 ± 14.5% of CTR; **p < 0.01; Fig. 2e) were elevated in cholinergic neurons (DIV10) upon nerve growth factor (NGF) administration (NGF; 100 ng/ml, 30′)

Summary

Introduction

The basal forebrain cholinergic system (BFCS) modulates many important behaviors, through robust inputs to the cortex and hippocampus [1, 2] and reciprocal feedback projections [3]. The cholinergic neurons of the medial septum, corresponding to the Ch1 subregion of the BFCS, modulate attention, reference and spatial memories, as well as learning in mice and humans [1, 4]. Synaptic failure and metabolic derangement in basal forebrain cholinergic neurons (BFCN) have been reported to parallel memory deficits in mild cognitive impairment (MCI) and in Alzheimer’s disease (AD) [5,6,7]. For this reason, it has been proposed as a good predictor of MCI progression toward AD [8]. Their high metabolic profile has been suggested to be the main cause of peculiar BFCN vulnerability in neurodegenerative diseases [9]

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Discussion

Conclusion