{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T18:30:39Z","timestamp":1793817039461,"version":"4.6.1"},"reference-count":66,"publisher":"Society for Neuroscience","issue":"20","license":[{"start":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T00:00:00Z","timestamp":1510876800000},"content-version":"vor","delay-in-days":206,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2017,5,17]]},"abstract":"<jats:p>Increasing evidence has suggested that systemic inflammation along with local brain inflammation can play a significant role in Alzheimer's disease (AD) pathogenesis. Identifying key molecules that regulate the crosstalk between the immune and the CNS can provide potential therapeutic targets. TNF-\u03b1 is a proinflammatory cytokine implicated in the pathogenesis of systemic inflammatory and neurodegenerative diseases, such as rheumatoid arthritis (RA) and AD. Recent studies have reported that anti-TNF-\u03b1 therapy or RA itself can modulate AD pathology, although the underlying mechanism is unclear. To investigate the role of peripheral TNF-\u03b1 as a mediator of RA in the pathogenesis of AD, we generated double-transgenic 5XFAD\/Tg197 AD\/TNF mice that develop amyloid deposits and inflammatory arthritis induced by human TNF-\u03b1 (huTNF-\u03b1) expression. We found that 5XFAD\/Tg197 mice display decreased amyloid deposition, compromised neuronal integrity, and robust brain inflammation characterized by extensive gliosis and elevated blood-derived immune cell populations, including phagocytic macrophages and microglia. To evaluate the contribution of peripheral huTNF-\u03b1 in the observed brain phenotype, we treated 5XFAD\/Tg197 mice systemically with infliximab, an anti-huTNF-\u03b1 antibody that does not penetrate the blood\u2013brain barrier and prevents arthritis. Peripheral inhibition of huTNF-\u03b1 increases amyloid deposition, rescues neuronal impairment, and suppresses gliosis and recruitment of blood-derived immune cells, without affecting brain huTNF-\u03b1 levels. Our data report, for the first time, a distinctive role for peripheral TNF-\u03b1 in the modulation of the amyloid phenotype in mice by regulating blood-derived and local brain inflammatory cell populations involved in \u03b2-amyloid clearance.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Mounting evidence supports the active involvement of systemic inflammation, in addition to local brain inflammation, in Alzheimer's disease (AD) progression. TNF-\u03b1 is a pluripotent cytokine that has been independently involved in the pathogenesis of systemic inflammatory rheumatoid arthritis (RA) and AD. Here we first demonstrate that manipulation of peripheral TNF-\u03b1 in the context of arthritis modulates the amyloid phenotype by regulating immune cell trafficking in the mouse brain. Our study suggests that additionally to its local actions in the AD brain, TNF-\u03b1 can also indirectly modulate amyloid pathology as a regulator of peripheral inflammation. Our findings may have significant implications in the treatment of RA patients with anti-TNF-\u03b1 drugs and in the potential use of TNF-targeted therapies for AD.<\/jats:p>","DOI":"10.1523\/jneurosci.2484-16.2017","type":"journal-article","created":{"date-parts":[[2017,4,26]],"date-time":"2017-04-26T00:40:26Z","timestamp":1493167226000},"page":"5155-5171","source":"Crossref","is-referenced-by-count":74,"title":["Peripheral Tumor Necrosis Factor-Alpha (TNF-\u03b1) Modulates Amyloid Pathology by Regulating Blood-Derived Immune Cells and Glial Response in the Brain of AD\/TNF Transgenic 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