Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging

Abstract

Peripheral insulin resistance is a key component of metabolic syndrome associated with obesity, dyslipidemia, hypertension, and type 2 diabetes. While the impact of insulin resistance is well recognized in the periphery, it is also becoming apparent in the brain. Recent studies suggest that insulin resistance may be a factor in brain aging and Alzheimer's disease (AD) whereby intranasal insulin therapy, which delivers insulin to the brain, improves cognition and memory in AD patients. Here, we tested a clinically relevant delivery method to determine the impact of two forms of insulin, short-acting insulin lispro (Humalog) or long-acting insulin detemir (Levemir), on cognitive functions in aged F344 rats. We also explored insulin effects on the Ca(2+)-dependent hippocampal afterhyperpolarization (AHP), a well-characterized neurophysiological marker of aging which is increased in the aged, memory impaired animal. Low-dose intranasal insulin improved memory recall in aged animals such that their performance was similar to that seen in younger animals. Further, because ex vivo insulin also reduced the AHP, our results suggest that the AHP may be a novel cellular target of insulin in the brain, and improved cognitive performance following intranasal insulin therapy may be the result of insulin actions on the AHP.

Novel calcium-related targets of insulin in hippocampal neurons

“…Indeed, there is evidence that insulin receptor numbers and their functions are decreased in aging and AD animal models (Zaia & Piantanelli, 1996; Frolich et al , 1998; Zhao et al , 2004; Zhao et al , 2008). At the cellular level, brain insulin deficiency and reduction in insulin signaling, perhaps mediated by insulin resistance, could represent one of the altered pathways linked to altered memory function or synaptic communication during aging and AD (Craft et al , 1996; Rasgon & Jarvik, 2004; de la Monte et al , 2006; Talbot et al , 2012; De Felice, 2013; Sasaoka et al , 2014; Maimaiti et al , 2016). One approach to combat this reduction in insulin signaling that has received much interest clinically is the use of intranasal insulin delivery to selectively increase insulin concentration in the brain (Born et al , 2002).…”

“…The intranasal route of insulin administration raises insulin acutely in the central nervous system without much risk of peripheral hypoglycemia (Kern et al , 1999; Ott et al , 2014; Lochhead et al , 2015; Anderson et al , 2016; Maimaiti et al , 2016). Intranasal insulin therapy has been shown to improve memory function in AD patients and in healthy individuals (Benedict et al , 2004; Reger et al , 2006; Hanson & Frey, 2008; Reger et al , 2008; Craft et al , 2012; Schioth et al , 2012b; Freiherr et al , 2013; Craft et al , 2017).…”

“…Intranasal insulin therapy has been shown to improve memory function in AD patients and in healthy individuals (Benedict et al , 2004; Reger et al , 2006; Hanson & Frey, 2008; Reger et al , 2008; Craft et al , 2012; Schioth et al , 2012b; Freiherr et al , 2013; Craft et al , 2017). Further, animal models of aging and AD also show the positive impact of intranasal insulin in combating cognitive decline (Francis et al , 2008; Marks et al , 2009; Apostolatos et al , 2012; de la Monte, 2013; Adzovic et al , 2015; Salameh et al , 2015; Anderson et al , 2016; Maimaiti et al , 2016). Despite these promising outcomes, the mechanisms of action in the brain, and specifically on neurons of the hippocampus where insulin plays a recognizable role in learning and memory (Zhao et al , 1999; Zhao et al , 2004), remain largely unknown.…”

Insulin potentiates the therapeutic effect of memantine against central STZ-induced spatial learning and memory deficit

“…Insulin therapy in this study showed that even in sAD that insulin receptors are damaged, exogenous insulin administration seems to act effectively. Systemically administered insulin causes blood glucose changes so recently and in clinical trials, intranasal insulin is used to deliver insulin to the brain without affecting blood glucose [27][28][29][30]. The result of this study shows that icv administered insulin is protective in sAD animal model.…”

Fight against Glucose Rescues Age-Related Cognitive Decline

“…Besides, insulin triggers the clathrin-dependent endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, regulating the long-term depression [21] . A recent report indicates that the improved memory recall in rats after intranasal insulin administration may due to the amelioration of the age-related increase of Ca 2+ -dependent hippocampal after hyperpolarization, a well-characterized neurophysiological indicator of aging [23] . In AD, insulin action has been shown to decrease the burden of β-amyloid and hyperphosphorylation of tau, thus alleviate the pathological hallmarks (i. e., amyloid plaques and helical neurofibrillary tangles) [24] .…”