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

Abstract

BackgroundChronic 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.MethodsTo investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer’s disease mice (harboring PS1M146V, APPSwe, and tauP301L 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.Results3,6′-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.ConclusionsThese 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.

Reference and working memory deficits in the 3xTg-AD mouse between 2 and 15-months of age: A cross-sectional study

“…These findings support the results of Gabbita et al [28] who found that 3xTg-AD mice had significant working memory deficits in the radial arm maze. They also support the findings that 3xTg-AD mice have reference memory deficits in the MWM [20,[29][30][31][32][33][34].…”

“…To date, only one study has examined working and reference memory of 3xTg-AD mice. Using the win-shift paradigm in the radial arm maze, Gabbita et al [28] found that 6-month old 3xTg-AD mice made significantly more working memory errors than B6129SF2/J controls, but did not differ in number of reference memory errors. Most studies investigating spatial reference memory in the 3xTg-AD mice using the Morris water maze (MWM) found no reference memory deficits at 2 months of age [29][30][31][32][33], although Stover et al [34] reported learning deficits in 3xTg -AD mice in the MWM at 2 months of age.…”

3,6′‐dithiothalidomide improves experimental stroke outcome by suppressing neuroinflammation

“…Interestingly, we found that both T and 3,6′-DT reduced brain damage and improved functional outcome when administered prior to MCAO/R, but only 3,6′-DT was effective when treatment was delayed for 3 hr after the stroke. This differential efficacy of T and 3,6′-DT with delayed treatment may be the result of the different abilities to enter and be retained within the brain, in line with the ability of 3,6′-DT but not T to lower brain TNF levels and improve cognition in an animal model of Alzheimer’s disease (Gabbita et al, 2012). …”

Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents

“…Inhibition of TNFa activity ameliorated AD-like pathology and cognitive impairment in AD animal models. Thalidomide, a TNFa inhibitor, significantly attenuated neuroinflammation, Ab deposition, and tau phosphorylation ) and improved memory function (Gabbita et al 2012). Infliximab, the antibody against TNFa, reduced the levels of TNFa, amyloid plaques, and tau phosphorylation in transgenic mice (Shi et al 2011a).…”