Details

Autor(en) / Beteiligte

• MONTGOMERY, Sara L
• MASTRANGELO, Michael A
• HABIB, Diala
• NARROW, Wade C
• KNOWLDEN, Sara A
• WRIGHT, Terry W
• BOWERS, William J

Titel

Ablation of TNF-RI/RII Expression in Alzheimer's Disease Mice Leads to an Unexpected Enhancement of Pathology: Implications for Chronic Pan-TNF-α Suppressive Therapeutic Strategies in the Brain

Ist Teil von

• The American journal of pathology, 2011-10, Vol.179 (4), p.2053-2070

Ort / Verlag

Bethesda, MD: American Society for Investigative Pathology

Erscheinungsjahr

2011

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss and cognitive impairment. Neuroinflammation, including the extensive production of pro-inflammatory molecules and the activation of microglia, has been implicated in the disease process. Tumor necrosis factor (TNF)-α, a prototypic pro-inflammatory cytokine, is elevated in AD, is neurotoxic, and colocalizes with amyloid plaques in AD animal models and human brains. We previously demonstrated that the expression of TNF-α is increased in AD mice at ages preceding the development of hallmark amyloid and tau pathological features and that long-term expression of this cytokine in these mice leads to marked neuronal death. Such observations suggest that TNF-α signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-α receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-α receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-α. These mice exhibit enhanced amyloid and tau-related pathological features by the age of 15 months, in stark contrast to age-matched 3xTg-AD counterparts. Moreover, 3xTg-ADxTNF-RI/RII knock out-derived primary microglia reveal reduced amyloid-β phagocytic marker expression and phagocytosis activity, indicating that intact TNF-α receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-β peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-α inhibitors for the treatment of AD.