Intranasal insulin improves cognition and modulates β-amyloid in early AD

Reger, Mark A.; Watson, G. Stennis; Green, P. S.; Wilkinson, Charles W.; Baker, Laura D.; Cholerton, Brenna; Fishel, Mark A.; Plymate, Stephen R.; Breitner, John C.S.; DeGroodt, William; Mehta, Pankaj; Craft, Suzanne

doi:10.1212/01.wnl.0000265401.62434.36

Cited by 737 publications

(571 citation statements)

References 31 publications

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“…Recent reports are consistent with the possibility that one such protective mechanism could be provided by CNS insulin signaling. Insulin plays a key role in plasticity mechanisms in the CNS (26,27) and it recently has been shown that insulin and the insulin-sensitizing drug rosiglitazone improve cognitive performance in mouse models of AD and in patients with early AD (28)(29)(30). Conversely, insulin-resistant type 2 diabetes patients show significantly increased risk for developing AD (31).…”

mentioning

confidence: 99%

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

Felice

Vieira

Bomfim³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

587

490

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Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Aβ) oligomers. Mechanistically, soluble Aβ oligomers, also referred to as Aβ-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.

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mentioning

confidence: 99%

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

Felice

Vieira

Bomfim³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

587

490

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“…Specifically, studies that have involved the intranasal infusion of insulin (i.e. direct delivery of insulin into the central nervous system) have suggested that insulin administration can enhance memory performance in the absence of changes in plasma glucose or insulin (Reger et al, 2006;Reger, Watson, Green, Wilkinson et al, 2008). Craft and colleagues (1994) observed a gender difference in glucose facilitation of memory, in that glucose was observed to facilitate episodic memory in males, but this effect was not observed in female participants.…”

Section: Insulinmentioning

confidence: 99%

Glucose enhancement of human memory: A comprehensive research review of the glucose memory facilitation effect

Smith

Riby

Eekelen

et al. 2011

Neuroscience & Biobehavioral Reviews

133

123

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The brain relies upon glucose as its primary fuel. In recent years, a rich literature has developed from both human and animal studies indicating that increases in circulating blood glucose can facilitate cognitive functioning. This phenomenon has been termed the 'glucose memory facilitation effect'. The purpose of this review is to discuss a number of salient studies which have investigated the influence of glucose ingestion on neurocognitive performance in individuals with a) compromised neurocognitive capacity, as well as b) normally functioning individuals (with a focus on research conducted with human participants). The proposed neurocognitive mechanisms purported to underlie the modulatory effect of glucose on neurocognitive performance will also be considered. Many theories have focussed upon the hippocampus, given that this brain region is heavily implicated in learning and memory. Further, it will be suggested that glucose is a possible mechanism underlying the phenomenon that enhanced memory performance is typically observed for emotionally laden stimuli.

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“…Systemic or intranasal administration of insulin enhances learning and memory and has been proposed as a treatment for Alzheimer's disease [68]. These findings have led to the hypothesis that insulin insufficiency may lead to the defects in neurocognition commonly observed in MDD (discussed below).…”

Section: Endocrinological Factorsmentioning

confidence: 99%

Type 1 diabetes mellitus and major depressive disorder: evidence for a biological link

et al. 2011

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Aims/hypothesis A growing body of research suggests that the prevalence of major depressive disorder (MDD) in children and youth with type 1 diabetes mellitus is significantly higher than that of youth without type 1 diabetes and is associated with increased illness severity. The objective of this article is to review the current literature on the pathophysiology of these two common diseases with respect to potential areas of overlapping biological dysfunction. Methods A search of English language articles published between 1966 and 2010 was conducted and augmented with manual review of reference lists from the identified publications. Results The evidence suggests plausible mechanisms whereby a biological relationship between type 1 diabetes and MDD may exist. These include the effects of circulating cytokines associated with autoimmune diabetes, the direct impact of insulin deficiency on neurogenesis/neurotransmitter metabolism, the effects of the chronic hyperglycaemic state, occurrence of iatrogenic hypoglycaemia and the impact of basal hyperactivity of the hypothalamic-pituitary-adrenal axis. Major depressive disorder (MDD) is highly prevalent among children and adolescents with type 1 diabetes mellitus. The prevalence of MDD among youth with type 1 diabetes (20-27%) is at least two to three times greater than the 5-8% background rate of MDD reported for non-diabetic youth [1, 2]. Early-onset MDD is severe, and in combination with diabetes (the third most common chronic disease in childhood), is associated with poorer diabetes control, increased Conclusions/interpretation

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Intranasal insulin improves cognition and modulates β-amyloid in early AD

Abstract: The results of this pilot study support further investigation of the benefits of intranasal insulin for patients with Alzheimer disease, and suggest that intranasal peptide administration may be a novel approach to the treatment of neurodegenerative disorders.

Cited by 737 publications

References 31 publications

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

Glucose enhancement of human memory: A comprehensive research review of the glucose memory facilitation effect

Type 1 diabetes mellitus and major depressive disorder: evidence for a biological link

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