Istradefylline reduces memory deficits in aging mice with amyloid pathology

Adenosine A(2A) receptors are putative therapeutic targets for neurological disorders. The adenosine A(2A) receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A(2A) 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 A beta, C-terminal fragments of the amyloid precursor protein (APP), or amyloid plaques, but not overexpression of APP per se, increase astrocytic A(2A) 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, A(2A) receptor blockers might help counteract memory problems in patients with Alzheimer's disease.