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Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier.
Zhou, Andrew L; Swaminathan, Suresh K; Salian, Vrishali S; Wang, Lushan; Curran, Geoffry L; Min, Hoon-Ki; Lowe, Val J; Kandimalla, Karunya K.
Afiliação
  • Zhou AL; Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States.
  • Swaminathan SK; Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States.
  • Salian VS; Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States.
  • Wang L; Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, United States.
  • Curran GL; Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States.
  • Min HK; Department of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States.
  • Lowe VJ; Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States.
  • Kandimalla KK; Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, United States.
Mol Pharm ; 21(5): 2176-2186, 2024 May 06.
Article em En | MEDLINE | ID: mdl-38625027
ABSTRACT
The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-ß (Aß) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased Aß 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 Aß 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 Aß peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125I]iodo-Aß42 decreased upon AG1024 treatment. Additionally, the brain influx of [125I]iodoinsulin, [125I]iodo-Aß42, [125I]iodo-Aß40, 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-Aß42, and [125I]iodo-Aß40 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 Aß and insulin trafficking receptors (LRP-1 and IR-ß). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aß 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 Aß accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Transdução de Sinais / Peptídeos beta-Amiloides / Insulina Limite: Animals Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Barreira Hematoencefálica / Transdução de Sinais / Peptídeos beta-Amiloides / Insulina Limite: Animals Idioma: En Revista: Mol Pharm Assunto da revista: BIOLOGIA MOLECULAR / FARMACIA / FARMACOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos