Lack of Widespread BBB Disruption in Alzheimer's Disease Models: Focus on Therapeutic Antibodies

被引：150

作者：

Bien-Ly, Nga ^{[1
]}

Boswell, C. Andrew ^{[2
]}

Jeet, Surinder ^{[3
]}

Beach, Thomas G. ^{[7
]}

Hoyte, Kwame ^{[4
]}

Luk, Wilman ^{[4
]}

Shihadeh, Vera ^{[4
]}

Ulufatu, Sheila ^{[2
]}

Foreman, Oded ^{[5
]}

Lu, Yanmei ^{[4
]}

DeVoss, Jason ^{[3
]}

van der Brug, Marcel ^{[6
]}

Watts, Ryan J. ^{[1
]}

机构：

[1] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Dev Sci, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Translat Immunol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Diagnost Discovery, San Francisco, CA 94080 USA

[7] Banner Sun Hlth Res Inst, Sun City, AZ 85372 USA

来源：

NEURON | 2015年 / 88卷 / 02期

关键词：

BLOOD-BRAIN-BARRIER; TRANSGENIC MICE; NEURODEGENERATIVE DISEASE; DYSFUNCTION; DEMENTIA; BETA; PERMEABILITY; TRANSPORT; TAUOPATHY; TAU;

D O I：

10.1016/j.neuron.2015.09.036

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

The blood-brain barrier (BBB) limits brain uptake of therapeutic antibodies. It is believed that the BBB is disrupted in Alzheimer's disease (AD), potentially increasing drug permeability de facto. Here we compared active versus passive brain uptake of systemically dosed antibodies (anti-transferrin receptor [TfR] bispecific versus control antibody) in mouse models of AD. We first confirmed BBB disruption in a mouse model of multiple sclerosis as a positive control. Importantly, we found that BBB permeability was vastly spared in mouse models of AD, including PS2-APP, Tau transgenics, and APOE4 knockin mice. Brain levels of TfR in mouse models or in human cases of AD resembled controls, suggesting target engagement of TfR bispecific is not limited. Furthermore, infarcts from human AD brain showed similar occurrences compared to age-matched controls. These results question the widely held view that the BBB is largely disrupted in AD, raising concern about assumptions of drug permeability in disease.

引用

页码：289 / 297

页数：9

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