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

被引：100

作者：

Steeland, Sophie ^{[1
,2
]}

Gorle, Nina ^{[1
,2
]}

Vandendriessche, Charysse ^{[1
,2
]}

Balusu, Sriram ^{[1
,2
]}

Brkic, Marjana ^{[1
,2
,3
]}

Van Cauwenberghe, Caroline ^{[1
,2
]}

Van Imschoot, Griet ^{[1
,2
]}

Van Wonterghem, Elien ^{[1
,2
]}

De Rycke, Riet ^{[1
,2
]}

Kremer, Anneke ^{[1
,2
,4
]}

Lippens, Saskia ^{[1
,2
,4
]}

Stopa, Edward ^{[5
,6
]}

Johanson, Conrad E. ^{[6
]}

Libert, Claude ^{[1
,2
]}

Vandenbroucke, Roosmarijn E. ^{[1
,2
]}

机构：

[1] VIB Ctr Inflammat Res, Ghent, Belgium

[2] Univ Ghent, Dept Biomed Mol Biol, Ghent, Belgium

[3] Univ Belgrade, Inst Biol Res, Dept Neurobiol, Belgrade, Serbia

[4] VIB BioImaging Core, Ghent, Belgium

[5] Rhode Isl Hosp, Dept Pathol, Providence, RI 02902 USA

[6] Brown Univ, Warren Alpert Med Sch, Dept Neurosurg, Providence, RI USA

来源：

EMBO MOLECULAR MEDICINE | 2018年 / 10卷 / 04期

关键词：

Alzheimer's disease; blood-CSF barrier; choroid plexus; therapy; TNF receptor 1; AMYLOID-BETA OLIGOMERS; NECROSIS-FACTOR-ALPHA; CHOROID-PLEXUS; BLOOD-BRAIN; GLUTAMATE RELEASE; GENETIC DELETION; MEMORY DEFICITS; GLIAL RESPONSE; FACTOR DEATH; MICE LEADS;

D O I：

10.15252/emmm.201708300

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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) AO 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.

引用

页数：22

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