Endocytosis of insulin at the blood-brain barrier

Pemberton, Sarah; Galindo, Demi; Schwartz, Michael W.; Banks, William A.; Rhea, Elizabeth M.

doi:10.3389/fddev.2022.1062366

Cited by 8 publications

(7 citation statements)

References 35 publications

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“…Also, the contribution of clathrin endocytosis was found for Aβ 42 and pS8-Aβ 42 , but less pronounced than for iso-Aβ 42 . The involvement of clathrin-dependent endocytosis in transport of proteins from the bloodstream to the brain was previously shown for transferrin and insulin receptors (Roberts et al, 1992 ; Goulatis and Shusta, 2017 ; Ayloo and Gu, 2019 ; Pemberton et al, 2022 ), but not for beta-amyloid peptides. There is also evidence that LRP-1 can mediate Aβ transport in both directions (Pflanzner et al, 2011 ).…”

Section: Discussionmentioning

confidence: 78%

Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model

Varshavskaya,

Petrushanko,

Mitkevich

et al. 2024

Front. Mol. Neurosci.

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One of the hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue (pS8-Aβ42) crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

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Section: Discussionmentioning

confidence: 78%

Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model

Varshavskaya,

Petrushanko,

Mitkevich

et al. 2024

Front. Mol. Neurosci.

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show abstract

Section: Discussionmentioning

confidence: 84%

Post-translational Modifications of Beta-Amyloid Alter Its Transport across the Blood-Brain Barrier

Varshavskaya,

Petrushanko,

Mitkevich

et al. 2023

Preprint

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One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of beta-amyloid peptide (Aβ) leading to formation of soluble neurotoxic Aβ oligomers and insoluble amyloid plaques in various parts of the brain. Aβ undergoes post-translational modifications that alter its pathogenic properties. Aβ is produced not only in brain, but also in the peripheral tissues. Such Aβ, including its post-translationally modified forms, can enter the brain from circulation by binding to RAGE and contribute to the pathology of AD. However, the transport of modified forms of Aβ across the blood–brain barrier (BBB) has not been investigated. Here, we used a transwell BBB model as a controlled environment for permeability studies. We found that Aβ42 containing isomerized Asp7 residue (iso-Aβ42) and Aβ42 containing phosphorylated Ser8 residue crossed the BBB better than unmodified Aβ42, which correlated with different contribution of endocytosis mechanisms to the transport of these isoforms. Using microscale thermophoresis, we observed that RAGE binds to iso-Aβ42 an order of magnitude weaker than to Aβ42. Thus, post-translational modifications of Aβ increase the rate of its transport across the BBB and modify the mechanisms of the transport, which may be important for AD pathology and treatment.

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“…Contrarily, impaired internalization can reduce insulin sensitivity by prolonging the exposure time of receptors to ligand, thereby promoting desensitization [23]. Previous studies investigated the mechanisms of insulin internalization at the level of the blood-brain barrier, with varying results [14,35]. Here, we sought to contextualize the role of hyperinsulinemia in aberrant insulin receptor internalization into brain endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells

DiLucia,

Kendrick,

Sims-Robinson

2023

IJMS

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Adequate perfusion of cerebral tissues, which is necessary for the preservation of optimal brain health, depends on insulin signaling within brain endothelial cells. Proper insulin signaling relies on the regulated internalization of insulin bound to the insulin receptor, a process which is disrupted by hyperinsulinemia via an unknown mechanism. Thus, the goal of this study was to characterize the impact of hyperinsulinemia on the regulation of molecular targets involved in cerebral blood flow and insulin receptor internalization into brain endothelial cells. The phosphorylation of molecular targets associated with cerebral blood flow and insulin receptor internalization was assessed in hyperinsulinemic brain endothelial cells. Insulin receptor uptake into cells was also examined in the setting of endocytosis blockade. Our data demonstrate that hyperinsulinemia impairs the activation of endothelial nitric oxide synthase. These data correspond with an impairment in clathrin-mediated endocytosis of the insulin receptor and dysregulated phosphorylation of key internalization effectors. We conclude that hyperinsulinemia alters the phosphorylation of molecular targets involved in clathrin-mediated endocytosis, disrupts signaling through the insulin receptor, and hinders the capacity for blood flow regulation by brain endothelial cells.

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Endocytosis of insulin at the blood-brain barrier

Cited by 8 publications

References 35 publications

Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model

Post-translational modifications of beta-amyloid alter its transport in the blood-brain barrier in vitro model

Post-translational Modifications of Beta-Amyloid Alter Its Transport across the Blood-Brain Barrier

Hyperinsulinemia Impairs Clathrin-Mediated Endocytosis of the Insulin Receptor and Activation of Endothelial Nitric Oxide Synthase in Brain Endothelial Cells

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