RETRACTED: Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy

Francis, George J.; Martinez, José A.; Liu, Wei Q.; Xu, Kevin; Ayer, Amit; Fine, Jared M.; Tuor, Ursula I.; Glazner, Gordon W.; Hanson, Leah R.; Frey, William H.; Toth, Cory

doi:10.1093/brain/awn288

Cited by 149 publications

(61 citation statements)

References 116 publications

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“…The role of impaired brain insulin signalling in the pathogenesis of AD is also supported by several recent studies showing improvements in cognition and memory by treatment with insulin or insulin sensitizers in AD patients [52–54] and in rodent models of AD and diabetes [55,56]. It is interesting to note that rosiglitazone, an anti-diabetic drug that increases insulin sensitivity, improves attention and memory in a subgroup of AD patients who do not carry the apoE4 allele [57].…”

Section: Discussionmentioning

confidence: 90%

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Liu

Grundke‐Iqbal

et al. 2011

The Journal of Pathology

421

337

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Brain glucose metabolism is impaired in Alzheimer’s disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin–PI3K–AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM–AD and seven control cases. We found decreases in the levels and activities of several components of the insulin–PI3K–AKT signalling pathway in AD and T2DM cases. The deficiency of insulin–PI3K–AKT signalling was more severe in individuals with both T2DM and AD (T2DM–AD). This decrease in insulin–PI3K–AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin–PI3K–AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin–PI3K–AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin–PI3K–AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer’s disease.

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Section: Discussionmentioning

confidence: 90%

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Liu

Grundke‐Iqbal

et al. 2011

The Journal of Pathology

421

337

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Introductionmentioning

confidence: 99%

Novel calcium-related targets of insulin in hippocampal neurons

et al. 2017

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Both insulin signaling disruption and Ca2+ dysregulation are closely related to memory loss during aging and increase the vulnerability to Alzheimer's disease (AD). In hippocampal neurons, aging-related changes in calcium regulatory pathways have been shown to lead to higher intracellular calcium levels and an increase in the Ca2+-dependent afterhyperpolarization (AHP), which is associated with cognitive decline. Recent studies suggest that insulin reduces the Ca2+-dependent AHP. Given the sensitivity of neurons to insulin and evidence that brain insulin signaling is reduced with age, insulin-mediated alterations in calcium homeostasis may underlie the beneficial actions of insulin in the brain. Indeed, increasing insulin signaling in the brain via intranasal delivery has yielded promising results such as improving memory in both clinical and animal studies. However, while several mechanisms have been proposed, few have focused on regulation on intracellular Ca2+. In the present study, we further examined the effects of acute insulin on calcium pathways in primary hippocampal neurons in culture. Using the whole-cell patch-clamp technique, we found that acute insulin delivery reduced voltage-gated calcium currents. Fura-2 imaging was used to also address acute insulin effects on spontaneous and depolarization-mediated Ca2+ transients. Results indicate that insulin reduced Ca2+ transients, which appears to have involved a reduction in ryanodine receptor function. Together, these results suggest insulin regulates pathways that control intracellular Ca2+ which may reduce the AHP and improve memory. This may be one mechanism contributing to improved memory recall in response to intranasal insulin therapy in the clinic.

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“…First, DM and dementia diagnosis were self-reported or reported by a proxy with a dichotomous response. Thus, it is unclear whether participants had type I or type II DM; however, impaired insulin regulation in type I DM has been associated with cognitive decline, as well (Francis et al ., 2008). Also, the study did not record diagnosis of pre-diabetes, duration of DM, use of insulin, or degree of DM control, all of which have been associated with cognitive performance (Elias et al ., 1997; Roberts et al ., 2008; Cholerton et al ., 2013).…”

Section: Discussionmentioning

confidence: 99%

Diabetes and cognitive outcomes in a nationally representative sample: the National Health and Aging Trends Study

Wennberg

Gottesman

Kaufmann

et al. 2014

Int. Psychogeriatr.

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Background The prevalence of both type II diabetes mellitus (DM) and cognitive impairment is high and increasing in older adults. We examined the extent to which DM diagnosis was associated with poorer cognitive performance and dementia diagnosis in a population-based cohort of US older adults. Methods We studied 7,606 participants in the National Health and Aging Trends Study, a nationally representative cohort of Medicare beneficiaries aged 65 years and older. DM and dementia diagnosis were based on self-report from participants or proxy respondents, and participants completed a word-list memory test, the Clock Drawing Test, and gave a subjective assessment of their own memory. Results In unadjusted analyses, self-reported DM diagnosis was associated with poorer immediate and delayed word recall, worse performance on the Clock Drawing Test, and poorer self-rated memory. After adjusting for demographic characteristics, body mass index, depression and anxiety symptoms, and medical conditions, DM was associated with poorer immediate and delayed word recall and poorer self-rated memory, but not with the Clock Drawing Test performance or self-reported dementia diagnosis. After excluding participants with a history of stroke, DM diagnosis was associated with poorer immediate and delayed word recall and the Clock Drawing Test performance, and poorer self-rated memory, but not with self-reported dementia diagnosis. Conclusions In this recent representative sample of older Medicare enrollees, self-reported DM was associated with poorer cognitive test performance. Findings provide further support for DM as a potential risk factor for poor cognitive outcomes. Studies are needed that investigate whether DM treatment prevents cognitive decline.

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RETRACTED: Intranasal insulin prevents cognitive decline, cerebral atrophy and white matter changes in murine type I diabetic encephalopathy

Cited by 149 publications

References 116 publications

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes

Novel calcium-related targets of insulin in hippocampal neurons

Diabetes and cognitive outcomes in a nationally representative sample: the National Health and Aging Trends Study

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