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

EMBO Molecular Medicine

Conrad E Johanson¹  Edward Stopa²  Griet Van Imschoot³  Saskia Lippens³  Sriram Balusu³  Elien Van Wonterghem³  Sophie Steeland³  Marjana Brkic³  Riet De Rycke³  Roosmarijn E Vandenbroucke³  Nina Gorlé³  Claude Libert³  Charysse Vandendriessche³  Caroline Van Cauwenberghe³  Anneke Kremer³ 

[1] Department of Neurosurgery Warren Alpert Medical School of Brown University Providence Rhode Island USA;Department of Pathology Rhode Island Hospital Providence Rhode Island USA;VIB Center for Inflammation Research Ghent Belgium;

关键词: Alzheimer's disease;    blood‐CSF barrier;    choroid plexus;    therapy;    TNF receptor 1;   

DOI  :  10.15252/emmm.201708300

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown