A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer’s disease mouse model

Tumor necrosis factor-α (TNF-α) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer’s disease (AD). Although the linkage between increased TNF-α levels and AD is widely recognized, TNF-α–neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic Aβ-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid β deposition and β-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of Aβ. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates Aβ-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.

Tumor necrosis factor-α (TNF-α) is a master proinflammatory cytokine involved in the regulation of innate and adaptive immunity (1). TNF-α plays a crucial role in various autoimmune and neurological disorders, including Alzheimer’s disease (AD) (2, 3). TNF-α–neutralizing therapeutics have been approved for the treatment of different inflammatory and autoimmune diseases, like rheumatoid arthritis or plaque psoriasis (4). However, the treatment of neurological disorders with TNF-α–neutralizing drugs led to inconclusive or even detrimental results (5–8). The latter could be explained, at least partly, by the different functions of the two receptors of TNF: on the one hand, stimulation of cytotoxic and strongly inflammatory pathways by TNF receptor 1 (TNFR1) in response to soluble TNF (sTNF) or membrane TNF (mTNF) or, on the other hand, activation of TNF receptor 2 (TNFR2) by mTNF eliciting pro- and antiinflammatory effects but also neuroprotective functions and tissue regeneration (9, 10).As a consequence, several studies aimed at selective targeting of TNFR1 or TNFR2, instead of completely inhibiting TNF-α. First, targeting TNFR1 by using specific TNFR1 antagonists or sTNF inhibitors resulted in amelioration of inflammation and apoptosis in various in vivo neurodegenerative disease models, such as models of multiple sclerosis (11, 12), Parkinson’s disease (13), and AD (14, 15). Second, targeting TNFR2 by specific TNFR2 agonists exerted an enhancement in neuroregeneration and tissue homeostasis in vitro (16) as well as in in vivo models (17). Therefore, specific targeting of TNFR1 and/or TNFR2 offers a promising new therapeutic avenue.However, clinical and preclinical studies on the effect of specific therapeutic targeting of TNFR2 in AD are lacking. It is acknowledged that during AD, the deposition of Aβ plaques, one of the main hallmarks of AD pathogenesis, occurs as a consequence of an imbalance between Aβ production and clearance (18). The β-secretase 1 (BACE-1) is mainly responsible for the production of toxic Aβ peptides, whereas uptake and degradation of these peptides are achieved by glial cells in the central nervous system (CNS), such as microglia and astrocytes (19, 20). Microglia are the resident macrophages of the CNS and their function is to constantly survey their environment and react to any detected insult, such as tissue damage or pathogen infection (21). Microglia are also involved in tissue repair and maintaining brain homeostasis. Moreover, microglia have been found to be essential for Aβ clearance in AD mouse models (20). It has been reported that in the context of AD, BACE-1 expression is increased, and the presence of Aβ plaques impairs the phagocytic activity of microglia (22, 23). These events could lead to an overproduction of Aβ accompanied by reduced Aβ clearance, which may partly lead to the observed pathogenesis of AD.Previous studies have proven that TNFR2 activation is neuroprotective in different disease models; however, it remains to be established whether TNFR2 stimulation has a protective effect against Aβ-mediated neuropathology and amyloid deposition and if this could improve cognitive functions. Therefore, in this study, we tested the hypothesis that selective stimulation of TNFR2 is able to abrogate Aβ-associated neuropathology and cognitive impairments.