PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease

Nat Med. 2016 Feb;22(2):135-7. doi: 10.1038/nm.4022. Epub 2016 Jan 18.

Abstract

Systemic immune suppression may curtail the ability to mount the protective, cell-mediated immune responses that are needed for brain repair. By using mouse models of Alzheimer's disease (AD), we show that immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway evokes an interferon (IFN)-γ-dependent systemic immune response, which is followed by the recruitment of monocyte-derived macrophages to the brain. When induced in mice with established pathology, this immunological response leads to clearance of cerebral amyloid-β (Aβ) plaques and improved cognitive performance. Repeated treatment sessions were required to maintain a long-lasting beneficial effect on disease pathology. These findings suggest that immune checkpoints may be targeted therapeutically in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / immunology*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / drug effects
  • Amyloid beta-Peptides / immunology
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Antibodies / pharmacology*
  • Behavior, Animal / drug effects*
  • Brain / drug effects*
  • Brain / immunology
  • Brain / pathology
  • Cognition / drug effects
  • Disease Models, Animal
  • Flow Cytometry
  • Humans
  • Immunohistochemistry
  • Interferon-gamma / drug effects
  • Interferon-gamma / immunology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Maze Learning / drug effects
  • Memory / drug effects*
  • Mice
  • Mice, Transgenic
  • Plaque, Amyloid / immunology*
  • Plaque, Amyloid / pathology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology*
  • Sequence Analysis, RNA
  • Signal Transduction / drug effects

Substances

  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Antibodies
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Interferon-gamma