The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old APP/PS1 Mice

Abstract

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD).In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-␤ (A␤), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP swe /PS1 dE9 transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma A␤ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF A␤ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma A␤, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on A␤ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate A␤ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma A␤ in young and old mice, independent of neuronal insulin signaling.

The neuronal insulin receptor in its environment

“…). Since insulin concentrations in the synaptic cleft have not been measured during neuronal activity, it is difficult to tell if insulin levels near brain IRs vary enough to modulate their activation over the short term; however, very sharp increases in serum insulin (higher than those seen in the healthy post‐prandial condition) have no effect at all on total brain insulin content (Banks et al ., ) nor on hippocampus interstitial fluid concentration in mice (Stanley et al ., ).…”

“…Whole tissue rat hippocampus insulin concentration is 9 pM (Gomes et al 2009), interstitial fluid insulin concentration in mouse hippocampus is~10 pM (Stanley et al 2016), and human cerebrospinal fluid concentration~7 pM (Born et al 2002), within the range of activation of the homodimeric IR and possibly of hybrid receptors (Li et al 2005;Belfiore et al 2009). However, even if the unknown synaptic cleft concentration of insulin is somewhat higher, it is almost certainly not high enough to activate homodimeric IGF-1R (Belfiore et al 2009).…”

“…However, while a transmitterlike release of insulin from neurogliaform cells has recently been shown (Moln ar et al 2014), it appears that at most a small fraction of insulin in the brain (outside the hypothalamus) derives from rapid release by brain cells; the main fraction of brain insulin is probably transported over the blood-brain barrier and then diffuses passively (Gray et al 2014). Since insulin concentrations in the synaptic cleft have not been measured during neuronal activity, it is difficult to tell if insulin levels near brain IRs vary enough to modulate their activation over the short term; however, very sharp increases in serum insulin (higher than those seen in the healthy post-prandial condition) have no effect at all on total brain insulin content (Banks et al, 1997) nor on hippocampus interstitial fluid concentration in mice (Stanley et al, 2016).…”

Type-2-diabetes Alters CSF but not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys

“…Conversely, systemic hyperinsulinemia at post-prandial or supraphysiological levels, only modestly increase ISF Aβ levels. This suggests that changes in glucose, rather than insulin, correlates more closely with brain Aβ levels [10]. Although these studies suggest a mechanistic link between T2D and AD, rodent models of AD do not fully recapitulate the human course of disease, and it is important to translate these observations to primates.…”

“…While both are considered diseases of aging and mechanisms linking the two conditions remain elusive, epidemiological and cross-sectional studies suggest that individuals with T2D have a 2 -4 fold increased risk for developing AD and dementia and show increased AD pathology [6][7][8]. Preclinical studies in mouse models of cerebral amyloidosis suggest that systemic hyperglycemia increases Aβ levels within the hippocampal interstitial fluid (ISF) by 25%; an effect that is amplified when plaques are already present in the brain during the hyperglycemia challenge [9,10]. Moreover, mouse plasma glucose, ISF glucose, and ISF Aβ are highly correlated, and elevated glucose levels drive Aβ production in the hippocampus, in an activity dependent manner [9].…”