Publication date: 22/02/2018
Alzheimer’s disease (AD) is the most common form of dementia and increasing evidence has shown that neuroinflammation is an important and early hallmark of the pathogenesis. It has been suggested that tumor necrosis factor (TNF), a pro-inflammatory cytokine, might be detrimental in AD, though the results coming from clinical trials on anti-TNF inhibitors are inconclusive. Prof. Roosmarijn Vandenbroucke (VIB-UGent) reports in the authorative journal EMBO Molecular Medicine that TNF, via activation of its receptor TNFR1, is the main inflammatory upstream mediator of the AD-associated changes at the choroid plexus and that targeting TNF/TNFR1 signaling has therapeutic potential.
Prof. Vandenbroucke and her VIB-UGent research team focus since a few years on an often neglected structure in the brain called the choroid plexus which contains a monolayer of tightly connected choroid plexus epithelial (CPE) cells forming the blood-cerebrospinal fluid (CSF) barrier. Previous research from the team has shown that AD is associated with changes in CPE cell morphology and a compromised blood-CSF barrier. Now, based on gene expression analysis of choroid plexus tissue of AD patients compared to healthy persons and subsequent mouse studies, they found this specific role of TNF.
Prof. Roosmarijn Vandenbroucke (VIB-UGent): “We could confirm the detrimental role of TNF/TNFR1 signaling in two murine AD models: intracerebroventricular (icv) of oligomerized amyloid beta and transgenic APP/PS1 mice. TNFR1 contributes to the morphological damage of CPE cells in AD and TNFR1 abrogation reduces brain inflammation and prevents blood–CSF barrier impairment. In APP/PS1 transgenic mice, TNFR1 deficiency ameliorated amyloidosis and improved microgliosis. Strikingly, genetic and pharmacological blockage of TNFR1 with an in-house generated Nanobody did not only prevent the AD-associated inflammation, it also rescued against the induced cognitive impairments. Therefore, our data indicate that TNFR1 is a promising therapeutic target for AD treatment.”
An important limitation of the current study is the fact that the anti-TNFR1 Nanobody® was directly injected into the brain, thereby circumventing one of the major challenges of successful therapy for central nervous system (CNS) disorders: drug delivery across the tight brain barriers.
Prof. Roosmarijn Vandenbroucke (VIB-UGent): “To address this, we are currently focusing on novel potential strategies to deliver therapeutics into the brain. For this, we exploit the CPE cells as delivery route. Within the European Horizon 2020 B-SMART project and a recently granted SBO project, we are generating Nanobodies against different targets involved in transport across the blood-CSF barrier. After identification of an ideal candidate, this Nanobody will be coupled to nanoparticles that carry RNA therapeutics to target Alzheimer’s disease and of course also to the TNFR1-inhibiting Nanobody used in our current study.”