Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer's disease

EMBO Molecular Medicine
Sophie SteelandRoosmarijn E Vandenbroucke

Abstract

Alzheimer's disease (AD) is the most common form of dementia, and neuroinflammation is an important hallmark of the pathogenesis. Tumor necrosis factor (TNF) might be detrimental in AD, though the results coming from clinical trials on anti-TNF inhibitors are inconclusive. TNFR1, one of the TNF signaling receptors, contributes to the pathogenesis of AD by mediating neuronal cell death. The blood-cerebrospinal fluid (CSF) barrier consists of a monolayer of choroid plexus epithelial (CPE) cells, and AD is associated with changes in CPE cell morphology. Here, we report that TNF is the main inflammatory upstream mediator in choroid plexus tissue in AD patients. This was confirmed in two murine AD models: transgenic APP/PS1 mice and intracerebroventricular (icv) AβO injection. 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. Ultimately, genetic and pharmacological blockage of TNFR1 rescued from the induced cognitive impairments. Our data indicate that TNFR1 is a promising therapeutic target for AD treatment.

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Citations

Feb 26, 2019·Neural Regeneration Research·Sophie Steeland, Roosmarijn E Vandenbroucke
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Datasets Mentioned

BETA
GSE110226

Methods Mentioned

BETA
transgenic
transmission
scanning electron microscopy
electron microscopy
transmission electron microscopy
ELISA
Protein Assay
scanning

Software Mentioned

Imaris
IPA
TargetScan
GraphPad Prism
BitPlane
geNorm
Zen
ImageJ
ingenuity pathway analysis
GraphPad

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