Istradefylline reduces memory deficits in aging mice with amyloid pathology

Neurobiol Dis. 2018 Feb;110:29-36. doi: 10.1016/j.nbd.2017.10.014. Epub 2017 Oct 31.

Abstract

Adenosine A2A receptors are putative therapeutic targets for neurological disorders. The adenosine A2A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A2A receptors on neurons and astrocytes may contribute to Alzheimer's disease (AD) by impairing memory. However, it is not known whether istradefylline enhances cognitive function in aging animals with AD-like amyloid plaque pathology. Here, we show that elevated levels of Aβ, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A2A receptor levels in the hippocampus and neocortex of aging mice. Moreover, in amyloid plaque-bearing mice, low-dose istradefylline treatment enhanced spatial memory and habituation, supporting the conclusion that, within a well-defined dose range, A2A receptor blockers might help counteract memory problems in patients with Alzheimer's disease.

Keywords: Adenosine receptors; Alzheimer's disease; Amyloid plaques; Antagonist; Astrocytes; Behavior; Inhibition; Istradefylline; Memory; Therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine A2 Receptor Antagonists / pharmacology*
  • Aging
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides
  • Animals
  • Astrocytes / metabolism*
  • Brain / drug effects*
  • Brain / pathology
  • Female
  • Humans
  • Male
  • Memory Disorders*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Plaque, Amyloid / pathology
  • Purines / pharmacology*
  • Receptor, Adenosine A2A

Substances

  • Adenosine A2 Receptor Antagonists
  • Adora2a protein, mouse
  • Amyloid beta-Peptides
  • Purines
  • Receptor, Adenosine A2A
  • istradefylline