Blockade of α4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease

Sci Rep. 2019 Aug 19;9(1):12055. doi: 10.1038/s41598-019-48538-x.

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-β (Aβ) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1+ vessels in 3xTg-AD transgenic mice, which develop both Aβ and tau pathologies. The counter-ligand of VCAM-1 - α4β1 integrin, also known as very late antigen-4 (VLA-4) - was more abundant on circulating CD4+ T cells and was also expressed by a significant proportion of blood CD8+ T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that α4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block α4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, Aβ load and tau hyperphosphorylation. Our results demonstrate that α4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of α4 integrins may offer a new therapeutic strategy in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / diagnosis
  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / etiology*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Biomarkers
  • Cell Communication*
  • Disease Models, Animal
  • Endothelium / metabolism*
  • Gene Expression Regulation
  • Immunohistochemistry
  • Integrin alpha4 / antagonists & inhibitors*
  • Integrin alpha4 / genetics
  • Integrin alpha4 / metabolism
  • Leukocytes / metabolism*
  • Maze Learning
  • Memory*
  • Mice
  • Mice, Transgenic
  • Plaque, Amyloid / metabolism
  • Plaque, Amyloid / pathology
  • Treatment Outcome
  • tau Proteins / metabolism

Substances

  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • Biomarkers
  • tau Proteins
  • Integrin alpha4