title: 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.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY14642, USA. william_bowers@urmc.rochester.edu
authors.forename: Sara L
authors.initials: SL
authors.lastname: Montgomery
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mastrangelo
authors.forename: Diala
authors.initials: D
authors.lastname: Habib
authors.forename: Wade C
authors.initials: WC
authors.lastname: Narrow
authors.forename: Sara A
authors.initials: SA
authors.lastname: Knowlden
authors.forename: Terry W
authors.initials: TW
authors.lastname: Wright
authors.forename: William J
authors.initials: WJ
authors.lastname: Bowers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D000682:Amyloid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D056654:CA3 Region, Hippocampal / Q000473:pathology / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003433:Crosses, Genetic; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D010587:Phagocytosis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics
chemical_list: C545487:APP protein, human; D048868:Adaptor Proteins, Signal Transducing; C491049:Aif1 protein, mouse; D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D002135:Calcium-Binding Proteins; D018950:Lipopolysaccharide Receptors; D008840:Microfilament Proteins; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C119675:Sirpb1a protein, mouse; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins