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Multiple clinical studies implicate tumor necrosis factor-\u03b1 as an inflammatory mediator of neurodegeneration in patients with Alzheimer\u2019s because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer\u2019s 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To investigate the effect of early immune modulation on neuroinflammation and cognitive outcome, we treated triple transgenic Alzheimer\u2019s disease mice (harboring PS1<jats:sub>M146V<\/jats:sub>, APP<jats:sub>Swe<\/jats:sub>, and tau<jats:sub>P301L<\/jats:sub>transgenes) with the small molecule tumor necrosis factor-\u03b1 inhibitors, 3,6\u2032-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-\u03b1. After 10\u2009weeks of treatment, cognitive performance was assessed using radial arm maze and neuroinflammation was assessed using biochemical, stereological and flow cytometric endpoints.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>3,6\u2032-dithiothalidomide reduced tumor necrosis factor-\u03b1 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.<\/jats:p><jats:p>In comparison to non-transgenic controls, triple transgenic Alzheimer\u2019s disease mice had increased total numbers of infiltrating peripheral monomyelocytic\/granulocytic leukocytes with enhanced intracytoplasmic tumor necrosis factor-\u03b1, which was reduced after treatment with 3,6\u2032-dithiothalidomide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results suggest that modulation of tumor necrosis factor-\u03b1 with small molecule inhibitors is safe and effective with potential for the long-term prevention and treatment of Alzheimer\u2019s disease.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1742-2094-9-99","type":"journal-article","created":{"date-parts":[[2012,6,1]],"date-time":"2012-06-01T08:51:21Z","timestamp":1338540681000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":80,"title":["Early intervention with a small molecule inhibitor for tumor nefosis factor-\u03b1 prevents cognitive deficits in a triple transgenic mouse model of Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"9","author":[{"given":"S Prasad","family":"Gabbita","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minu K","family":"Srivastava","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pirooz","family":"Eslami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming F","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi K","family":"Kobritz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Tweedie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nigel H","family":"Greig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank P","family":"Zemlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sherven P","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni E","family":"Harris-White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2012,5,25]]},"reference":[{"key":"578_CR1_578","doi-asserted-by":"publisher","first-page":"3666","DOI":"10.1073\/pnas.72.9.3666","volume":"72","author":"EA Carswell","year":"1975","unstructured":"Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B: An endotoxin- induced serum factor that causes necrosis of tumors. 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