A TNF receptor 2 agonist ameliorates neuropathology and improves cognition in an Alzheimer's disease mouse model

被引：24

作者：

Orti-Casan, Natalia ^{[1
]}

Zuhorn, Inge S. ^{[2
]}

Naude, Petrus J. W. ^{[1
,3
]}

De Deyn, Peter P. ^{[3
]}

van Schaik, Pauline E. M. ^{[4
]}

Wajant, Harald ^{[5
]}

Eisel, Ulrich L. M. ^{[1
]}

机构：

[1] Univ Groningen, Groningen Inst Evolutionary Life Sci, Dept Mol Neurobiol, NL-9747 AG Groningen, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Dept Biomed Engn, NL-9713 AV Groningen, Netherlands

[3] Univ Groningen, Univ Med Ctr Groningen, Dept Neurol & Alzheimer Ctr, NL-9713 AV Groningen, Netherlands

[4] Univ Groningen, Univ Med Ctr Groningen, Sect Mol Neurobiol, Dept Biomed Sci Cells & Syst, NL-9713 AV Groningen, Netherlands

[5] Univ Wurzburg, Dept Internal Med 2, D-97070 Wurzburg, Germany

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2022年 / 119卷 / 37期

关键词：

Alzheimer's disease; TNF; neuroinflammation; TNFR2; agonist; 20 mouse model; BLOOD-BRAIN-BARRIER; REGULATORY T-CELLS; ACTIVATION; MICROGLIA; BACE1; INFLAMMATION; CLEARANCE; INHIBITOR; DEFICITS; ALPHA;

D O I：

10.1073/pnas.2201137119

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic, proinflammatory cytokine related to different neurodegenerative diseases, including Alzheimer's disease (AD). Although the linkage between increased TNF-alpha levels and AD is widely recognized, TNF-alpha-neutralizing therapies have failed to treat AD. Previous research has associated this with the antithetic functions of the two TNF receptors, TNF receptor 1, associated with inflammation and apoptosis, and TNF receptor 2 (TNFR2), associated with neuroprotection. In our study, we investigated the effects of specifically stimulating TNFR2 with a TNFR2 agonist (NewStar2) in a transgenic A beta-overexpressing mouse model of AD by administering NewStar2 in two different ways: centrally, via implantation of osmotic pumps, or systemically by intraperitoneal injections. We found that both centrally and systemically administered NewStar2 resulted in a drastic reduction in amyloid beta deposition and beta-secretase 1 expression levels. Moreover, activation of TNFR2 increased microglial and astrocytic activation and promoted the uptake and degradation of A beta. Finally, cognitive functions were also improved after NewStar2 treatment. Our results demonstrate that activation of TNFR2 mitigates A beta-induced cognitive deficits and neuropathology in an AD mouse model and indicates that TNFR2 stimulation might be a potential treatment for AD.

引用

页数：11

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