Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model

被引：4

作者：

Zelek, Wioleta M. ^{[1
]}

Bevan, Ryan J. ^{[1
]}

Nimmo, Jacqui ^{[1
]}

Dewilde, Maarten ^{[2
,3
]}

De Strooper, Bart ^{[4
,5
,6
]}

Morgan, Bryan Paul ^{[1
]}

机构：

[1] Cardiff Univ, UK Dementia Res Inst Cardiff, Sch Med, Cardiff CF14 4XN, Wales

[2] Katholieke Univ Leuven, Therapeut & Diagnost Antibodies, Pharmaceut & Pharmacol Sci, B-3000 Leuven, Belgium

[3] Katholieke Univ Leuven, Antibody Ctr, PharmAbs, B-3000 Leuven, Belgium

[4] Katholieke Univ Leuven, Ctr Brain & Dis Res, B-3000 Leuven, Belgium

[5] VIB Leuven, B-3000 Leuven, Belgium

[6] UCL, UK Dementia Res Inst, London, England

来源：

BRAIN | 2025年 / 148卷 / 03期

基金：

英国医学研究理事会; 欧洲研究理事会;

关键词：

neuroinflammation; therapy; drug delivery; blood-brain barrier; mouse model; MEMBRANE ATTACK COMPLEX; INFLAMMATION; ANTIBODY; REGIONS; BINDING; SYSTEM; DOMAIN; MICE;

D O I：

10.1093/brain/awae278

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Complement activation is implicated in driving brain inflammation, self-cell damage and progression of injury in Alzheimer's disease and other neurodegenerative diseases. Here, we investigate the impact of brain delivery of a complement-blocking antibody on neurodegeneration in an Alzheimer's mouse model. We engineered a brain-penetrant recombinant antibody targeting the pro-inflammatory membrane attack complex.Systemic administration of this antibody in APPNL-G-F mice reduced brain levels of complement activation products, demonstrating successful brain entry and target engagement. Prolonged treatment decreased synapse loss, amyloid burden and brain inflammatory cytokine levels, concomitant with cognitive improvement compared to controls. These results underscore the potential of brain-penetrant complement-inhibiting drugs as promising therapeutics, targeting downstream of amyloid plaques in Alzheimer's disease. Zelek et al. develop a brain-penetrant recombinant antibody that targets the pro-inflammatory membrane attack complex. In an Alzheimer's disease mouse model, systemic administration of this antibody lowered brain levels of complement activation products, and reduced neurodegeneration, synapse loss, and amyloid burden.

引用

页码：941 / 954

页数：14

共 62 条

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Zelek, Wioleta M. ;

Xie, Long ;

Morgan, B. Paul ;

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MOLECULAR IMMUNOLOGY, 2019, 114 :341-352

[62] Extracting the barbs from complement assays: Identification and optimisation of a safe substitute for traditional buffers [J].

Zelek, Wioleta M. ;

Harris, Claire L. ;

Morgan, B. Paul .

IMMUNOBIOLOGY, 2018, 223 (12) :744-749

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