Therapeutic B-cell depletion reverses progression of Alzheimer's disease

被引:155
作者
Kim, Ki [1 ]
Wang, Xin [1 ]
Ragonnaud, Emeline [1 ]
Bodogai, Monica [1 ]
Illouz, Tomer [2 ,3 ,4 ]
DeLuca, Marisa [1 ]
McDevitt, Ross A. [5 ]
Gusev, Fedor [6 ]
Okun, Eitan [2 ,3 ,4 ]
Rogaev, Evgeny [6 ,7 ,8 ,9 ]
Biragyn, Arya [1 ]
机构
[1] NIA, Immunoregulat Sect, Lab Immunol & Mol Biol, Baltimore, MD 21224 USA
[2] Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel
[3] Bar Ilan Univ, Gonda Brain Res Ctr, Ramat Gan, Israel
[4] Bar Ilan Univ, Paul Feder Lab Alzheimers Dis Res, Ramat Gan, Israel
[5] NIA, Mouse Phenotyping Unit, Comparat Med Sect, Baltimore, MD USA
[6] Russian Acad Sci, Inst Gen Genet, Dept Genom & Human Genet, Moscow, Russia
[7] Lomonosov Moscow State Univ, Fac Biol, Fac Bioengn & Bioinformat, Ctr Genet & Genet Technol, Moscow, Russia
[8] Univ Massachusetts, Sch Med, Dept Psychiat, Worcester, MA 01655 USA
[9] Sirius Univ Sci & Technol, Soci, Russia
关键词
TRANSGENIC MOUSE MODEL; A-BETA; MICROGLIAL ACTIVATION; COGNITIVE IMPAIRMENT; AMYLOID PATHOLOGY; MICE; IMMUNOGLOBULIN; INFLAMMATION; TRAFFICKING; HYPOTHESIS;
D O I
10.1038/s41467-021-22479-4
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
The function of B cells in Alzheimer's disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (A beta) may interfere with plaque formation and hence progression of the disease, B cells may contribute beyond merely producing immunoglobulins. Here we show that AD is associated with accumulation of activated B cells in circulation, and with infiltration of B cells into the brain parenchyma, resulting in immunoglobulin deposits around A beta plaques. Using three different murine transgenic models, we provide counterintuitive evidence that the AD progression requires B cells. Despite expression of the AD-fostering transgenes, the loss of B cells alone is sufficient to reduce A beta plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGF beta (+) microglia, respectively. Moreover, therapeutic depletion of B cells at the onset of the disease retards AD progression in mice, suggesting that targeting B cells may also benefit AD patients. Alzheimer's disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.
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页数:11
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