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

• Published in: Nature communications Vol. 12; no. 1; pp. 2185 - 11
• Main Authors: Kim, Ki, Wang, Xin, Ragonnaud, Emeline, Bodogai, Monica, Illouz, Tomer, DeLuca, Marisa, McDevitt, Ross A., Gusev, Fedor, Okun, Eitan, Rogaev, Evgeny, Biragyn, Arya
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.04.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/51; 631/250/1619/40; 631/250/2520; 631/250/371; 692/699/375/132/1283; Accumulation; Alzheimer Disease - immunology; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; B-Lymphocytes - immunology; Dementia disorders; Depletion; Disease Progression; Female; Hippocampus - pathology; Humanities and Social Sciences; Humans; Immunoglobulins; Interleukin-1beta - metabolism; Lymphocyte Activation - immunology; Lymphocyte Depletion; Lymphocytes B; Memory cells; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia; Microglia - metabolism; multidisciplinary; Neurodegenerative diseases; Parenchyma; Phenotype; Plaque, Amyloid - metabolism; Science; Science (multidisciplinary); Senile plaques; Transforming Growth Factor beta - metabolism; Transgenes; Transgenic animals
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22479-4

The function of B cells in Alzheimer’s disease (AD) is not fully understood. While immunoglobulins that target amyloid beta (Aβ) 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 Aβ 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 Aβ plaque burden and disease-associated microglia. It reverses behavioral and memory deficits and restores TGFβ + 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.