Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease

David Tweedie, Ryan A. Ferguson, Kelly Fishman, Kathryn A. Frankola, Henriette Van Praag, Harold W. Holloway, Weiming Luo, Yazhou Li, Luca Caracciolo, Isabella Russo, Sergio Barlati, Balmiki Ray, Debomoy Lahiri, Francesca Bosetti, Nigel H. Greig, Susanna Rosi

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Background: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.Methods: The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ 1-42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide.Results: 3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ 1-42 peptide, prior systemic 3,6'-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.Conclusions: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

Original languageEnglish
Article number106
JournalJournal of Neuroinflammation
Volume9
DOIs
StatePublished - May 29 2012

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Alzheimer Disease
Animal Models
Tumor Necrosis Factor-alpha
Pathology
Inflammation
Lipopolysaccharides
Disease Progression
Synaptosomal-Associated Protein 25
3,6'-dithiothalidomide
tau Proteins
Synaptophysin
Neuronal Plasticity
Amyloid beta-Protein Precursor
Memory Disorders
Nitrites
Neurodegenerative Diseases
Pharmaceutical Preparations
Young Adult
Rodentia
Macrophages

Keywords

  • Alzheimer's disease
  • Amyoid-β peptide
  • Lenalidomide
  • Mild cognitive impairment
  • Neurodegeneration
  • Neuroinflammation
  • Neuroprotection
  • Tau
  • Thalidomide
  • Tnf-α

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Neurology
  • Immunology
  • Neuroscience(all)

Cite this

Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease. / Tweedie, David; Ferguson, Ryan A.; Fishman, Kelly; Frankola, Kathryn A.; Van Praag, Henriette; Holloway, Harold W.; Luo, Weiming; Li, Yazhou; Caracciolo, Luca; Russo, Isabella; Barlati, Sergio; Ray, Balmiki; Lahiri, Debomoy; Bosetti, Francesca; Greig, Nigel H.; Rosi, Susanna.

In: Journal of Neuroinflammation, Vol. 9, 106, 29.05.2012.

Research output: Contribution to journalArticle

Tweedie, D, Ferguson, RA, Fishman, K, Frankola, KA, Van Praag, H, Holloway, HW, Luo, W, Li, Y, Caracciolo, L, Russo, I, Barlati, S, Ray, B, Lahiri, D, Bosetti, F, Greig, NH & Rosi, S 2012, 'Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease', Journal of Neuroinflammation, vol. 9, 106. https://doi.org/10.1186/1742-2094-9-106
Tweedie, David ; Ferguson, Ryan A. ; Fishman, Kelly ; Frankola, Kathryn A. ; Van Praag, Henriette ; Holloway, Harold W. ; Luo, Weiming ; Li, Yazhou ; Caracciolo, Luca ; Russo, Isabella ; Barlati, Sergio ; Ray, Balmiki ; Lahiri, Debomoy ; Bosetti, Francesca ; Greig, Nigel H. ; Rosi, Susanna. / Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease. In: Journal of Neuroinflammation. 2012 ; Vol. 9.
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title = "Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease",
abstract = "Background: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.Methods: The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ 1-42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide.Results: 3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ 1-42 peptide, prior systemic 3,6'-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.Conclusions: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.",
keywords = "Alzheimer's disease, Amyoid-β peptide, Lenalidomide, Mild cognitive impairment, Neurodegeneration, Neuroinflammation, Neuroprotection, Tau, Thalidomide, Tnf-α",
author = "David Tweedie and Ferguson, {Ryan A.} and Kelly Fishman and Frankola, {Kathryn A.} and {Van Praag}, Henriette and Holloway, {Harold W.} and Weiming Luo and Yazhou Li and Luca Caracciolo and Isabella Russo and Sergio Barlati and Balmiki Ray and Debomoy Lahiri and Francesca Bosetti and Greig, {Nigel H.} and Susanna Rosi",
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T1 - Tumor necrosis factor-α synthesis inhibitor 3,6'-dithiothalidomide attenuates markers of inflammation, Alzheimer pathology and behavioral deficits in animal models of neuroinflammation and Alzheimer's disease

AU - Tweedie, David

AU - Ferguson, Ryan A.

AU - Fishman, Kelly

AU - Frankola, Kathryn A.

AU - Van Praag, Henriette

AU - Holloway, Harold W.

AU - Luo, Weiming

AU - Li, Yazhou

AU - Caracciolo, Luca

AU - Russo, Isabella

AU - Barlati, Sergio

AU - Ray, Balmiki

AU - Lahiri, Debomoy

AU - Bosetti, Francesca

AU - Greig, Nigel H.

AU - Rosi, Susanna

PY - 2012/5/29

Y1 - 2012/5/29

N2 - Background: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.Methods: The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ 1-42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide.Results: 3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ 1-42 peptide, prior systemic 3,6'-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.Conclusions: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

AB - Background: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.Methods: The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ 1-42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide.Results: 3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ 1-42 peptide, prior systemic 3,6'-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.Conclusions: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

KW - Alzheimer's disease

KW - Amyoid-β peptide

KW - Lenalidomide

KW - Mild cognitive impairment

KW - Neurodegeneration

KW - Neuroinflammation

KW - Neuroprotection

KW - Tau

KW - Thalidomide

KW - Tnf-α

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U2 - 10.1186/1742-2094-9-106

DO - 10.1186/1742-2094-9-106

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