Ablation of TNF-RI/RII Expression in Alzheimer's Disease Mice Leads to an Unexpected Enhancement of Pathology

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)-␣, 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-␣ 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-␣ signaling promotes AD pathogenesis and that therapeutics suppressing this cytokine's activity may be beneficial. To dissect TNF-␣ receptor signaling requirements in AD, we generated triple-transgenic AD mice (3xTg-AD) lacking both TNF-␣ receptor 1 (TNF-RI) and 2 (TNF-RII), 3xTg-ADxTNF-RI/RII knock out, the cognate receptors of TNF-␣. 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-␤ phagocytic marker expression and phagocytosis activity, indicating that intact TNF-␣ receptor signaling is critical for microglial-mediated uptake of extracellular amyloid-␤ peptide pools. Overall, our results demonstrate that globally ablated TNF receptor signaling exacerbates pathogenesis and argues against long-term use of pan-anti-TNF-␣ inhibitors for the treatment of

Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology

“…For instance, induction of the proinflammatory cytokines IL-1β, TNF-α, IL-6, and IFN-γ correlated with reduced Aβ deposition in AD mouse models (23)(24)(25)(26). Recently, TNF-α receptor ablation was shown to enhance AD pathology in transgenic mice, likely because of impaired Aβ phagocytosis (27). Additionally, activation of microglia has been reported to induce lysosome acidification and increased degradation of Aβ (28).…”

Microglia in Alzheimer’s disease

“…Moreover, mice overexpressing IL-6 (127) or IFN-γ (128) had enhanced microglial phagocytosis of Aβ accompanied by an increase in complement component mRNA levels, TNF-α, and other inflammatory mediators. TNF receptor (TNFR) deficiency in 3xTgAD mice was associated with increased amyloid deposition and enhanced tau phosphorylation (129). Moreover, microglia from TNFR-deficient 3xTgAD mice showed defective phagocytosis, highlighting the protective role of TNF-α in facilitating clearance mechanisms.…”

Inflammatory Cytokines and Alzheimer’s Disease: A Review from the Perspective of Genetic Polymorphisms

“…However, neuroprotective roles of TNF-a have also been reported, as long-term and non-specific inhibition of TNF-a signaling worsens the AD-related pathology in the brains of AD transgenic mice [80]. Correspondingly, TNF-a mediates the microglial phagocytosis of Ab [80]. Two types of TNF-a receptors (TNF-RI and TNF-RII) have been identified, and they activate different downstream pathways to mediate distinct biological effects.…”

“…Moreover, short-term anti-TNF-a treatment improves cognition in AD patients [78], probably by relieving the Ab pathology [79]. However, neuroprotective roles of TNF-a have also been reported, as long-term and non-specific inhibition of TNF-a signaling worsens the AD-related pathology in the brains of AD transgenic mice [80]. Correspondingly, TNF-a mediates the microglial phagocytosis of Ab [80].…”