Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells

A Key Role of TGF-β1

Giuseppe Caruso, Claudia G Fresta, Nicolò Musso, Mariaconcetta Giambirtone, Margherita Grasso, Simona F Spampinato, Sara Merlo, Filippo Drago, Giuseppe Lazzarino, Maria A Sortino, Susan M Lunte, Filippo Caraci

Research output: Contribution to journalArticle

Abstract

Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O₂-• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects.

Original languageEnglish
JournalCells
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 17 2019

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Carnosine
Oxidative stress
Oxidative Stress
Inflammation
Oligomers
Aptitude
Dipeptides
Scavenging
Microglia
Neuroprotective Agents
Cell death
Defense Mechanisms
Interleukin-1
Histidine
Amyloid
Interleukin-10
Free Radicals
Toxicity
Muscle
Brain

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Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells : A Key Role of TGF-β1. / Caruso, Giuseppe; Fresta, Claudia G; Musso, Nicolò; Giambirtone, Mariaconcetta; Grasso, Margherita; Spampinato, Simona F; Merlo, Sara; Drago, Filippo; Lazzarino, Giuseppe; Sortino, Maria A; Lunte, Susan M; Caraci, Filippo.

In: Cells, Vol. 8, No. 1, 17.01.2019.

Research output: Contribution to journalArticle

Caruso, G, Fresta, CG, Musso, N, Giambirtone, M, Grasso, M, Spampinato, SF, Merlo, S, Drago, F, Lazzarino, G, Sortino, MA, Lunte, SM & Caraci, F 2019, 'Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1', Cells, vol. 8, no. 1. https://doi.org/10.3390/cells8010064
Caruso, Giuseppe ; Fresta, Claudia G ; Musso, Nicolò ; Giambirtone, Mariaconcetta ; Grasso, Margherita ; Spampinato, Simona F ; Merlo, Sara ; Drago, Filippo ; Lazzarino, Giuseppe ; Sortino, Maria A ; Lunte, Susan M ; Caraci, Filippo. / Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells : A Key Role of TGF-β1. In: Cells. 2019 ; Vol. 8, No. 1.
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AU - Giambirtone, Mariaconcetta

AU - Grasso, Margherita

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AU - Drago, Filippo

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AB - Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric Aβ1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aβ oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O₂-• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1β, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-β1. Carnosine also prevented Aβ-induced neurodegeneration in mixed neuronal cultures challenged with Aβ oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-β receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aβ toxicity with a key role of TGF-β1 in mediating these protective effects.

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