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

Nat Commun. 2021 Apr 12;12(1):2185. doi: 10.1038/s41467-021-22479-4.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Alzheimer Disease / immunology*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • B-Lymphocytes / immunology*
  • Disease Progression*
  • Female
  • Hippocampus / pathology
  • Humans
  • Interleukin-1beta / metabolism
  • Lymphocyte Activation / immunology
  • Lymphocyte Depletion*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism
  • Phenotype
  • Plaque, Amyloid / metabolism
  • Transforming Growth Factor beta / metabolism

Substances

  • Amyloid beta-Peptides
  • Interleukin-1beta
  • Transforming Growth Factor beta