| First Author | Montgomery SL | Year | 2013 |
| Journal | Am J Pathol | Volume | 182 |
| Issue | 6 | Pages | 2285-97 |
| PubMed ID | 23567638 | Mgi Jnum | J:197372 |
| Mgi Id | MGI:5492228 | Doi | 10.1016/j.ajpath.2013.02.030 |
| Citation | Montgomery SL, et al. (2013) Chronic Neuron- and Age-Selective Down-Regulation of TNF Receptor Expression in Triple-Transgenic Alzheimer Disease Mice Leads to Significant Modulation of Amyloid- and Tau-Related Pathologies. Am J Pathol 182(6):2285-97 |
| abstractText | Neuroinflammation, through production of proinflammatory molecules and activated glial cells, is implicated in Alzheimer's disease (AD) pathogenesis. One such proinflammatory mediator is tumor necrosis factor alpha (TNF-alpha), a multifunctional cytokine produced in excess and associated with amyloid beta-driven inflammation and cognitive decline. Long-term global inhibition of TNF receptor type I (TNF-RI) and TNF-RII signaling without cell or stage specificity in triple-transgenic AD mice exacerbates hallmark amyloid and neurofibrillary tangle pathology. These observations revealed that long-term pan anti-TNF-alpha inhibition accelerates disease, cautions against long-term use of anti-TNF-alpha therapeutics for AD, and urges more selective regulation of TNF signaling. We used adeno-associated virus vector-delivered siRNAs to selectively knock down neuronal TNF-R signaling. We demonstrate divergent roles for neuronal TNF-RI and TNF-RII where loss of opposing TNF-RII leads to TNF-RI-mediated exacerbation of amyloid beta and Tau pathology in aged triple-transgenic AD mice. Dampening of TNF-RII or TNF-RI+RII leads to a stage-independent increase in Iba-1-positive microglial staining, implying that neuronal TNF-RII may act nonautonomously on the microglial cell population. These results reveal that TNF-R signaling is complex, and it is unlikely that all cells and both receptors will respond positively to broad anti-TNF-alpha treatments at various stages of disease. In aggregate, these data further support the development of cell-, stage-, and/or receptor-specific anti-TNF-alpha therapeutics for AD. |
