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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 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 DK, Bosetti F, Greig NH, Rosi S - J Neuroinflammation (2012)

Bottom Line: Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

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 A(β1-42) 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.

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Related in: MedlinePlus

3,6′-Dithiothalidomide (56 mg/kg i.p.) prevented Aβ1–42peptide-induced memory defects, neuronal cell degeneration and associated elevated CD11b staining of microglial cells. After 7 days of drug administration, aggregated Aβ1–42 peptide was administered directly into the CNS (and reverse peptide Aβ42–1 was utilized as a control) (for aggregation/aging process, see [32,41]). Mouse memory function was assessed by the Morris Water Maze; escape latencies measured over a 4-day trial period (A) and the final assessment undertaken 24 h after the last training session are shown (Bn = 8). (C) After the completion of behavioral assessments mice were euthanized, and the levels of neuronal degeneration were indicated by determining the level of Fluoro-Jade B labeling in the dentate gyrus; Aβ1–42 peptide induced a significant degree of dye incorporation that was attenuated by 3,6′-dithiothalidomide (n = 3–4). (D) Numbers of CD11b-positive cells in the CA3 hippocampus region were determined to be elevated only in the vehicle + Aβ1–42 group (n = 3–4). (E) Representative photomicrographs of Fluoro-Jade B-positive neurons in the dentate gyrus of control (vehicle-treated Aβ42–1-injected) mice, vehicle-treated Aβ1–42-injected mice and 3,6′-dithiothalidomide-treated Aβ1–42-injected mice. *Indicates comparisons with control (vehicle-treated Aβ42–1-injected) mice; #indicates comparisons with 3,6′-dithiothalidomide-treated Aβ1–42-injected mice (n = 3–4). Data are expressed as mean ± SEM of n observations; levels of statistical significance are indicated as follows: * or #P < 0.05, ** or ##P < 0.01, *** or ###P < 0.001.
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Figure 6: 3,6′-Dithiothalidomide (56 mg/kg i.p.) prevented Aβ1–42peptide-induced memory defects, neuronal cell degeneration and associated elevated CD11b staining of microglial cells. After 7 days of drug administration, aggregated Aβ1–42 peptide was administered directly into the CNS (and reverse peptide Aβ42–1 was utilized as a control) (for aggregation/aging process, see [32,41]). Mouse memory function was assessed by the Morris Water Maze; escape latencies measured over a 4-day trial period (A) and the final assessment undertaken 24 h after the last training session are shown (Bn = 8). (C) After the completion of behavioral assessments mice were euthanized, and the levels of neuronal degeneration were indicated by determining the level of Fluoro-Jade B labeling in the dentate gyrus; Aβ1–42 peptide induced a significant degree of dye incorporation that was attenuated by 3,6′-dithiothalidomide (n = 3–4). (D) Numbers of CD11b-positive cells in the CA3 hippocampus region were determined to be elevated only in the vehicle + Aβ1–42 group (n = 3–4). (E) Representative photomicrographs of Fluoro-Jade B-positive neurons in the dentate gyrus of control (vehicle-treated Aβ42–1-injected) mice, vehicle-treated Aβ1–42-injected mice and 3,6′-dithiothalidomide-treated Aβ1–42-injected mice. *Indicates comparisons with control (vehicle-treated Aβ42–1-injected) mice; #indicates comparisons with 3,6′-dithiothalidomide-treated Aβ1–42-injected mice (n = 3–4). Data are expressed as mean ± SEM of n observations; levels of statistical significance are indicated as follows: * or #P < 0.05, ** or ##P < 0.01, *** or ###P < 0.001.

Mentions: The direct administration of aged Aβ peptide, allowing its oligomerization, into the CNS of wild-type (wt) mice, was undertaken to emulate the inflammatory microenvironment of the AD brain. In our study, a single i.c.v. administration of Aβ1–42 was undertaken 7 days after the initiation of a daily schedule of systemic (i.p.) 3,6′-dithiothaliomide, utilizing a dose determined to be effective to ameliorate LPS-induced CNS elevations in TNF-α in the prior studies. Control animals were administered reverse peptide (with or without similar 3,6′-dithiothalidomide treatment). As illustrated in Figures 6A and B, Aβ1–42 alone induced a marked deficit in the learning ability of mice in the Morris Water Maze paradigm (for both acquisition and retention). This was accompanied by neuronal degeneration (assessed by Fluoro-Jade B staining) and an increased presence of CD11b-positive staining microglial cells within the dentate gyrus (DG) of the same animals (Figure 6C, D and E). Treatment of mice with 3,6′-dithiothalidomide, prior to Aβ1–42, markedly mitigated the actions of this toxic peptide. Specifically, drug-treated animals performed at a level similar to control mice in the Morris Water Maze, and showed evidence of reduced levels of both neuronal degeneration and CD11b positive microglial cells in comparison to Aβ1–42 alone mice. No differences were evident between mice administered Aβ42–1 with or without drug treatment in any of the measured parameters.


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 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 DK, Bosetti F, Greig NH, Rosi S - J Neuroinflammation (2012)

3,6′-Dithiothalidomide (56 mg/kg i.p.) prevented Aβ1–42peptide-induced memory defects, neuronal cell degeneration and associated elevated CD11b staining of microglial cells. After 7 days of drug administration, aggregated Aβ1–42 peptide was administered directly into the CNS (and reverse peptide Aβ42–1 was utilized as a control) (for aggregation/aging process, see [32,41]). Mouse memory function was assessed by the Morris Water Maze; escape latencies measured over a 4-day trial period (A) and the final assessment undertaken 24 h after the last training session are shown (Bn = 8). (C) After the completion of behavioral assessments mice were euthanized, and the levels of neuronal degeneration were indicated by determining the level of Fluoro-Jade B labeling in the dentate gyrus; Aβ1–42 peptide induced a significant degree of dye incorporation that was attenuated by 3,6′-dithiothalidomide (n = 3–4). (D) Numbers of CD11b-positive cells in the CA3 hippocampus region were determined to be elevated only in the vehicle + Aβ1–42 group (n = 3–4). (E) Representative photomicrographs of Fluoro-Jade B-positive neurons in the dentate gyrus of control (vehicle-treated Aβ42–1-injected) mice, vehicle-treated Aβ1–42-injected mice and 3,6′-dithiothalidomide-treated Aβ1–42-injected mice. *Indicates comparisons with control (vehicle-treated Aβ42–1-injected) mice; #indicates comparisons with 3,6′-dithiothalidomide-treated Aβ1–42-injected mice (n = 3–4). Data are expressed as mean ± SEM of n observations; levels of statistical significance are indicated as follows: * or #P < 0.05, ** or ##P < 0.01, *** or ###P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 6: 3,6′-Dithiothalidomide (56 mg/kg i.p.) prevented Aβ1–42peptide-induced memory defects, neuronal cell degeneration and associated elevated CD11b staining of microglial cells. After 7 days of drug administration, aggregated Aβ1–42 peptide was administered directly into the CNS (and reverse peptide Aβ42–1 was utilized as a control) (for aggregation/aging process, see [32,41]). Mouse memory function was assessed by the Morris Water Maze; escape latencies measured over a 4-day trial period (A) and the final assessment undertaken 24 h after the last training session are shown (Bn = 8). (C) After the completion of behavioral assessments mice were euthanized, and the levels of neuronal degeneration were indicated by determining the level of Fluoro-Jade B labeling in the dentate gyrus; Aβ1–42 peptide induced a significant degree of dye incorporation that was attenuated by 3,6′-dithiothalidomide (n = 3–4). (D) Numbers of CD11b-positive cells in the CA3 hippocampus region were determined to be elevated only in the vehicle + Aβ1–42 group (n = 3–4). (E) Representative photomicrographs of Fluoro-Jade B-positive neurons in the dentate gyrus of control (vehicle-treated Aβ42–1-injected) mice, vehicle-treated Aβ1–42-injected mice and 3,6′-dithiothalidomide-treated Aβ1–42-injected mice. *Indicates comparisons with control (vehicle-treated Aβ42–1-injected) mice; #indicates comparisons with 3,6′-dithiothalidomide-treated Aβ1–42-injected mice (n = 3–4). Data are expressed as mean ± SEM of n observations; levels of statistical significance are indicated as follows: * or #P < 0.05, ** or ##P < 0.01, *** or ###P < 0.001.
Mentions: The direct administration of aged Aβ peptide, allowing its oligomerization, into the CNS of wild-type (wt) mice, was undertaken to emulate the inflammatory microenvironment of the AD brain. In our study, a single i.c.v. administration of Aβ1–42 was undertaken 7 days after the initiation of a daily schedule of systemic (i.p.) 3,6′-dithiothaliomide, utilizing a dose determined to be effective to ameliorate LPS-induced CNS elevations in TNF-α in the prior studies. Control animals were administered reverse peptide (with or without similar 3,6′-dithiothalidomide treatment). As illustrated in Figures 6A and B, Aβ1–42 alone induced a marked deficit in the learning ability of mice in the Morris Water Maze paradigm (for both acquisition and retention). This was accompanied by neuronal degeneration (assessed by Fluoro-Jade B staining) and an increased presence of CD11b-positive staining microglial cells within the dentate gyrus (DG) of the same animals (Figure 6C, D and E). Treatment of mice with 3,6′-dithiothalidomide, prior to Aβ1–42, markedly mitigated the actions of this toxic peptide. Specifically, drug-treated animals performed at a level similar to control mice in the Morris Water Maze, and showed evidence of reduced levels of both neuronal degeneration and CD11b positive microglial cells in comparison to Aβ1–42 alone mice. No differences were evident between mice administered Aβ42–1 with or without drug treatment in any of the measured parameters.

Bottom Line: Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.

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 A(β1-42) 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.

Show MeSH
Related in: MedlinePlus