P1‐197: Amyloid Beta Effects on Insulin Permeability From Plasma to Brain Measured by I‐125 Insulin Spect in App/Ps1 Mice

Swaminathan, Suresh Kumar; Min, Hoon Ki; Sarma, Vidur V.; Ahlschwede, Kristen M.; Bruinsma, Tyler J.; Curran, Geoffry L.; Decklever, Teresa; Lowe, Val J.; Kandimalla, Karunya K.

doi:10.1016/j.jalz.2018.06.201

Cited by 2 publications

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“…Exposure to toxic Aβ peptides was reported to inhibit insulin signaling in a pattern similar to AG1024, a dual IGF1R/IR kinase inhibitor that decreased the phosphorylation of the insulin signaling kinases Akt and Erk in neurons . Previously, we reported that Aβ exposure inhibits both insulin signaling and insulin transcytosis at the BBB in mice. , Thus, we hypothesized that insulin signaling pathways are implicated in the mechanisms by which Aβ peptides inhibit insulin transcytosis at the BBB. To test this hypothesis, we showed that [ 125 I]iodoinsulin uptake to the brain from the systemic circulation decreased in healthy mice upon treatment with AG1024.…”

Section: Discussionmentioning

confidence: 93%

“…38 Previously, we reported that Aβ exposure inhibits both insulin signaling and insulin transcytosis at the BBB in mice. 31,39 Thus, we hypothesized that insulin signaling pathways are implicated in the mechanisms by which Aβ peptides inhibit insulin transcytosis at the BBB. To test this hypothesis, we showed that [ 125 I]iodoinsulin uptake to the brain from the systemic circulation decreased in healthy mice upon treatment with AG1024.…”

Section: ■ Discussionmentioning

confidence: 99%

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Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood–Brain Barrier

Zhou,

Swaminathan,

Salian

et al. 2024

Mol. Pharmaceutics

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The blood–brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-β (Aβ) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer’s disease (AD) brain, increased Aβ levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aβ and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of 125I radiolabeled Aβ peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125I]iodo-Aβ42 decreased upon AG1024 treatment. Additionally, the brain influx of [125I]iodoinsulin, [125I]iodo-Aβ42, [125I]iodo-Aβ40, and [125I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [125I]iodoinsulin, [125I]iodo-Aβ42, and [125I]iodo-Aβ40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aβ and insulin trafficking receptors (LRP-1 and IR-β). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aβ peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aβ accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.

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Section: Discussionmentioning

confidence: 93%

Section: ■ Discussionmentioning

confidence: 99%

Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood–Brain Barrier

Zhou,

Swaminathan,

Salian

et al. 2024

Mol. Pharmaceutics

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Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

Zhou

Sharda

Sarma

et al. 2022

JAD

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Background: Age is the most common risk factor for Alzheimer’s disease (AD), a neurodegenerative disorder characterized by the hallmarks of toxic amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Moreover, sub-physiological brain insulin levels have emerged as a pathological manifestation of AD. Objective: Identify age-related changes in the plasma disposition and blood-brain barrier (BBB) trafficking of Aβ peptides and insulin in mice. Methods: Upon systemic injection of 125I-Aβ 40, 125I-Aβ 42, or 125I-insulin, the plasma pharmacokinetics and brain influx were assessed in wild-type (WT) or AD transgenic (APP/PS1) mice at various ages. Additionally, publicly available single-cell RNA-Seq data [GSE129788] was employed to investigate pathways regulating BBB transport in WT mice at different ages. Results: The brain influx of 125I-Aβ 40, estimated as the permeability-surface area product, decreased with age, accompanied by an increase in plasma AUC. In contrast, the brain influx of 125I-Aβ 42 increased with age, accompanied by a decrease in plasma AUC. The age-dependent changes observed in WT mice were accelerated in APP/PS1 mice. As seen with 125I-Aβ 40, the brain influx of 125I-insulin decreased with age in WT mice, accompanied by an increase in plasma AUC. This finding was further supported by dynamic single-photon emission computed tomography (SPECT/CT) imaging studies. RAGE and PI3K/AKT signaling pathways at the BBB, which are implicated in Aβ and insulin transcytosis, respectively, were upregulated with age in WT mice, indicating BBB insulin resistance. Conclusion: Aging differentially affects the plasma pharmacokinetics and brain influx of Aβ isoforms and insulin in a manner that could potentially augment AD risk.

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P1‐197: Amyloid Beta Effects on Insulin Permeability From Plasma to Brain Measured by I‐125 Insulin Spect in App/Ps1 Mice

Cited by 2 publications

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Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood–Brain Barrier

Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood–Brain Barrier

Age-Dependent Changes in the Plasma and Brain Pharmacokinetics of Amyloid-β Peptides and Insulin

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