Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, CA 94158, USA.
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
Neurobiol Dis. 2018 Feb;110:29-36. doi: 10.1016/j.nbd.2017.10.014. Epub 2017 Oct 31.
Adenosine A receptors are putative therapeutic targets for neurological disorders. The adenosine A receptor antagonist istradefylline is approved in Japan for Parkinson's disease and is being tested in clinical trials for this condition elsewhere. A 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 A 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 receptor blockers might help counteract memory problems in patients with Alzheimer's disease.
腺苷 A 受体是神经紊乱的潜在治疗靶点。腺苷 A 受体拮抗剂伊曲茶碱在日本被批准用于治疗帕金森病，并正在其他地方的临床试验中针对该病症进行测试。神经元和星形胶质细胞上的 A 受体可能通过损害记忆而导致阿尔茨海默病（AD）。然而，目前尚不清楚伊曲茶碱是否会增强具有 AD 样淀粉样斑块病理的老年动物的认知功能。在这里，我们发现 Aβ、淀粉样前体蛋白（APP）的 C 端片段或淀粉样斑块的水平升高，但 APP 的过表达本身不会增加衰老小鼠海马体和新皮层中星形胶质细胞的 A 受体水平。此外，在携带淀粉样斑块的小鼠中，低剂量伊曲茶碱治疗增强了空间记忆和习惯形成，这支持了这样的结论，即在一个明确的剂量范围内，A 受体阻滞剂可能有助于缓解阿尔茨海默病患者的记忆问题。
