Nuclear factor-kappa B: Glucocorticoid-induced leucine zipper interface analogs suppress pathology in an Alzheimer's disease model

Mythily Srinivasan, Niloy Lahiri, Anish Thyagarajan, Emily Witek, Debra Hickman, Debomoy Lahiri

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Introduction: Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid β–induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model. Methods: GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors. Results: The brain tissues of GA-1– and GA-2–treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors. Discussion: The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)488-498
Number of pages11
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Volume4
DOIs
StatePublished - Jan 1 2018

Fingerprint

Leucine Zippers
NF-kappa B
Glucocorticoids
Alzheimer Disease
Gliosis
Pathology
Cytokines
Peptides
Brain
Amyloid
Amides
Lipopolysaccharides
Cell Culture Techniques
Therapeutics
Proteins
G(A1) ganglioside

Keywords

  • Alzheimer's disease
  • Neurodegeneration
  • Neuroinflammation
  • NF-κB p65 blockade
  • Peptide therapeutics

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

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title = "Nuclear factor-kappa B: Glucocorticoid-induced leucine zipper interface analogs suppress pathology in an Alzheimer's disease model",
abstract = "Introduction: Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid β–induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model. Methods: GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors. Results: The brain tissues of GA-1– and GA-2–treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors. Discussion: The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.",
keywords = "Alzheimer's disease, Neurodegeneration, Neuroinflammation, NF-κB p65 blockade, Peptide therapeutics",
author = "Mythily Srinivasan and Niloy Lahiri and Anish Thyagarajan and Emily Witek and Debra Hickman and Debomoy Lahiri",
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AU - Lahiri, Niloy

AU - Thyagarajan, Anish

AU - Witek, Emily

AU - Hickman, Debra

AU - Lahiri, Debomoy

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N2 - Introduction: Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid β–induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model. Methods: GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors. Results: The brain tissues of GA-1– and GA-2–treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors. Discussion: The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.

AB - Introduction: Glucocorticoid-induced leucine zipper is a regulatory protein that sequesters activated nuclear factor-kappa B p65. Previously, we showed that rationally designed analogs of the p65-binding domain of glucocorticoid-induced leucine zipper, referred to as glucocorticoid-induced leucine zipper analogs (GAs), inhibited amyloid β–induced metabolic activity and inflammatory cytokines in mixed brain cell cultures. Here, we investigate the therapeutic efficacy of GA in an Alzheimer's disease model. Methods: GA and control peptides were synthesized covalently as peptide amides with the cell-penetrating agent. C57Bl/6J mice induced with lipopolysaccharide-mediated neuroinflammation (250 mg/kg i.p/day for six days) were treated on alternate days with GA-1, GA-2, or control peptides (25 mg/kg i.v). Brain tissues were assessed for gliosis, cytokines, and antiapoptotic factors. Results: The brain tissues of GA-1– and GA-2–treated mice exhibited significantly reduced gliosis, suppressed inflammatory cytokines, and elevated antiapoptotic factors. Discussion: The antineuroinflammatory effects of GA suggest potential therapeutic application for Alzheimer's disease.

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