Choroid plexus tumor necrosis factor receptor 1: A new neuroinflammatory piece of the complex Alzheimer's disease puzzle

Abstract

Due to the aging of the population and despite the enormous scientific effort, Alzheimer's disease remains one of the biggest medical and pharmaceutical challenges in current medicine. Novel insights highlight the importance of neuroinflammation as an undeniable player in the onset and progression of Alzheimer's disease. Tumor necrosis factor is a master inflammatory cytokine that signals via tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2, but that also regulates several brain functions in health and disease. However, clinical trials investigating drugs that interfere with the tumor necrosis factor pathway in Alzheimer's disease led to inconclusive results, partially because not only the pro-inflammatory tumor necrosis factor/tumor necrosis factor receptor 1, but also the beneficial tumor necrosis factor/tumor necrosis factor receptor 2 signaling was antagonized in these trials. We recently found that tumor necrosis factor is the main upregulated cytokine in the choroid plexus of Alzheimer's disease patients, signaling via tumor necrosis factor receptor 1. In agreement with this, choroidal tumor necrosis factor/tumor necrosis factor receptor 1 signaling was also upregulated in different Alzheimer's disease mouse models. Interestingly, both genetic and nanobody-based pharmacological blockage of tumor necrosis factor receptor 1 signaling was accompanied by favorable effects on Alzheimer's disease-associated inflammation, choroidal morphology and cognitive functioning. Here, we briefly summarize the detrimental effects that can be mediated by tumor necrosis factor/tumor necrosis factor receptor 1 signaling in (early) Alzheimer's disease, and the consequences this might have on the disease progression. As the main hypothesis in Alzheimer's disease clinical trials is still based on the amyloid beta-cascade, the importance of Alzheimer's disease-associated neuroinflammation urge the development of novel therapeutic strategies that might be effective in the early stages of Alzheimer's disease and prevent the irreversible neurodegeneration and resulting memory decline.

Keywords: TNFR; blood-cerebrospinal fluid barrier; cognitive decline; drug development; mouse models; neurodegeneration; neuroinflammation; preclinical research; tumor necrosis factor.

Figure 1

Neuroinflammatory effects of tumor necrosis factor receptor 1 (TNFR1) in Alzheimer’s disease pathology in two Alzheimer’s disease mouse models. (A–H) In the acute Alzheimer’s disease mouse model, TNFR1^+/+ and TNFR1^–/– mice were intracerebroventricularly injected with amyloid beta oligomers (AβO) (A, B, E, F). In the transgenic mouse model amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic (tg) mice in a TNFR1^+/+ or TNFR1^–/– background were used (C, D, G, H). (A–D, F) Relative mRNA gene expression was determined by quantitative polymerase chain reaction in the choroid plexus (A, C, F) and hippocampus (b, d) 6 h after AβO injection (A, B, F) and in late-stage APP/PS1 transgenic mice (C, D). (E) Six hours after AβO injection, the blood-cerebrospinal fluid (CSF) barrier permeability was determined in wild type (WT) and TNFR1^–/– mice. (G) Brain sections of late-stage APP/PS1 mice were stained with Thioflavin-S to detect Aβ disposition in the whole brain, and a morphometric analysis was performed. (H) Whole-brain sections of APP/PS1 mice were stained with ionized calcium binding adapter molecule 1 (IBA-1) for microglia activation and the IBA-1⁺ cells were quantified by determining the brown staining. All graphs are adapted from Steeland et al. (2018b). Il6: Interleukin 6; Il1β: interleukin 1β; Tnf: tumor necrosis factor; Mmp8: matrix metalloproteinase-8; ns: no significance.

Figure 2

Schematic overview of the effects of choroid plexus TNFR1 in the pathology of Alzheimer’s disease. In the presence of toxic soluble amyloid beta oligomers (AβO), the choroid plexus gets inflamed and loses its morphologic characteristics. Activated TNF/TNFR1 signaling in the choroid plexus epithelial (CPE) cells results in the induction of inflammatory cytokines and matrix metalloproteinases, which is associated with disruption of the tight junction between the CPE cells. The inflammatory environment activates the microglia, which in turn also start secreting inflammatory mediators. Later in the pathology, amyloid beta (Aβ) plaques are found in the brain parenchyma, of which the formation is facilitated via TNF/TNFR1, and also the neurons get affected. Ultimately, these events lead to the typical memory decline. Both genetic (TNFR1^–/–) and pharmacological TNFR1 blockage (Nanobody TROS) can prevent these events and may form a new therapeutic in early Alzheimer’s disease. BBB: Blood-brain barrier; CSF: cerebrospinal fluid; MMP: matrix metalloproteinase; TNF: tumor necrosis factor; TNFR1: TNF receptor 1.