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Early intervention with a small molecule inhibitor for tumor necrosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Gabbita SP, Srivastava MK, Eslami P, Johnson MF, Kobritz NK, Tweedie D, Greig NH, Zemlan FP, Sharma SP, Harris-White ME - J Neuroinflammation (2012)

Bottom Line: Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints. 3,6'-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice.These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: P2D Bioscience, Cincinnati, OH 45242, USA.

ABSTRACT

Background: Chronic neuroinflammation is an important component of Alzheimer's disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer's because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer's disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.

Methods: To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer's disease mice (harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6'-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints.

Results: 3,6'-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice. In comparison to non-transgenic controls, triple transgenic Alzheimer's disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6'-dithiothalidomide.

Conclusions: These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease.

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Related in: MedlinePlus

Amyloid precursor protein/amyloid beta peptide staining is not changed in 3 × Tg mice by 3,6′-dithiothalidomide or thalidomide treatment. 6E10 immunohistochemistry was stereologically analyzed in the hippocampal CA1 to CA2 regions (left graph; n = 5 to 6 mice per treatment). There were no statistically significant differences in 6E10+ cell counts between treatment groups. Representative photomicrographs of each treatment group are shown. The same regions were also analyzed for optical density (right graph) and show that there were no differences between treatment groups.
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Figure 8: Amyloid precursor protein/amyloid beta peptide staining is not changed in 3 × Tg mice by 3,6′-dithiothalidomide or thalidomide treatment. 6E10 immunohistochemistry was stereologically analyzed in the hippocampal CA1 to CA2 regions (left graph; n = 5 to 6 mice per treatment). There were no statistically significant differences in 6E10+ cell counts between treatment groups. Representative photomicrographs of each treatment group are shown. The same regions were also analyzed for optical density (right graph) and show that there were no differences between treatment groups.

Mentions: The number of 6E10+ cells in the CA1 to CA2 region of the hippocampus was not changed by either Thal or 3,6′-DT treatment. Intraneuronal 6E10 staining was light at 6.5 months of age in the 3 × Tg mice with only an occasional diffuse plaque found and the majority of the staining was confined to cells in the hippocampus and cortex. Figure 8 shows representative sections of the CA1 to CA2 region of the hippocampus. Stereological counts of CA1 to CA2 did not reveal differences across treatment groups in either numbers of 6E10+ cells in this region or in 6E10 optical density. At 6.5 months of age, thioflavin S + deposits were not seen in the 3 × Tg mouse model [37] and none were observed in 6.5 month control 3 × Tg mice in this study. Treatment with Thal or 3,6′-DT did not alter this.


Early intervention with a small molecule inhibitor for tumor necrosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Gabbita SP, Srivastava MK, Eslami P, Johnson MF, Kobritz NK, Tweedie D, Greig NH, Zemlan FP, Sharma SP, Harris-White ME - J Neuroinflammation (2012)

Amyloid precursor protein/amyloid beta peptide staining is not changed in 3 × Tg mice by 3,6′-dithiothalidomide or thalidomide treatment. 6E10 immunohistochemistry was stereologically analyzed in the hippocampal CA1 to CA2 regions (left graph; n = 5 to 6 mice per treatment). There were no statistically significant differences in 6E10+ cell counts between treatment groups. Representative photomicrographs of each treatment group are shown. The same regions were also analyzed for optical density (right graph) and show that there were no differences between treatment groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3403851&req=5

Figure 8: Amyloid precursor protein/amyloid beta peptide staining is not changed in 3 × Tg mice by 3,6′-dithiothalidomide or thalidomide treatment. 6E10 immunohistochemistry was stereologically analyzed in the hippocampal CA1 to CA2 regions (left graph; n = 5 to 6 mice per treatment). There were no statistically significant differences in 6E10+ cell counts between treatment groups. Representative photomicrographs of each treatment group are shown. The same regions were also analyzed for optical density (right graph) and show that there were no differences between treatment groups.
Mentions: The number of 6E10+ cells in the CA1 to CA2 region of the hippocampus was not changed by either Thal or 3,6′-DT treatment. Intraneuronal 6E10 staining was light at 6.5 months of age in the 3 × Tg mice with only an occasional diffuse plaque found and the majority of the staining was confined to cells in the hippocampus and cortex. Figure 8 shows representative sections of the CA1 to CA2 region of the hippocampus. Stereological counts of CA1 to CA2 did not reveal differences across treatment groups in either numbers of 6E10+ cells in this region or in 6E10 optical density. At 6.5 months of age, thioflavin S + deposits were not seen in the 3 × Tg mouse model [37] and none were observed in 6.5 month control 3 × Tg mice in this study. Treatment with Thal or 3,6′-DT did not alter this.

Bottom Line: Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints. 3,6'-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice.These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease.

View Article: PubMed Central - HTML - PubMed

Affiliation: P2D Bioscience, Cincinnati, OH 45242, USA.

ABSTRACT

Background: Chronic neuroinflammation is an important component of Alzheimer's disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer's because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer's disease interventions are symptomatic treatments with limited efficacy that do not address etiology. Thus, a critical need exists for novel treatments directed towards modifying the pathophysiology and progression.

Methods: To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer's disease mice (harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes) with the small molecule tumor necrosis factor-α inhibitors, 3,6'-dithiothalidomide and thalidomide, beginning at four months of age. At this young age, mice do not exhibit plaque or tau pathology but do show mild intraneuronal amyloid beta protein staining and a robust increase in tumor necrosis factor-α. After 10 weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints.

Results: 3,6'-dithiothalidomide reduced tumor necrosis factor-α mRNA and protein levels in the brain and improved working memory performance and the ratio of resting to reactive microglia in the hippocampus of triple transgenic mice. In comparison to non-transgenic controls, triple transgenic Alzheimer's disease mice had increased total numbers of infiltrating peripheral monomyelocytic/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-α, which was reduced after treatment with 3,6'-dithiothalidomide.

Conclusions: These results suggest that modulation of tumor necrosis factor-α with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer's disease.

Show MeSH
Related in: MedlinePlus