[A drug targeting intracellular amyloid-β and oxidative stress: apomorphine]

Alzheimer's disease (AD) is the major cause of dementia in the elderly people. In the molecular pathogenesis of AD, toxicity of secreted amyloid-β protein (Aβ), especially Aβ oligomers, is considered to play a pivotal role. While, we have long been focused on intraneuronal Aβ as a therapeutic target in AD. Intraneuronal Aβ accumulation is found in the early stage of AD neurons, and may be quite toxic and pathogenic. Recently, we have found apomorphine (APO), a kind of dopamine receptor agonists, to promote the intracellular Aβ degradation activating the Aβ-degrading enzymes, proteasome and insulin-degrading enzyme (IDE). We then found that APO treatment improved memory function and AD-related pathology in an AD mouse model, 3xTg-AD mice. Moreover, APO protected against oxidative stress in vitro and in vivo. We further investigated effects of APO on cellular anti-oxidative stress system, and found that APO activated glutathione peroxidase (GPx) specifically. Thus, APO may be a promising drug for the cure of AD and clinical trials are necessary in the future. In addition, further investigation to understand the molecular mechanism associated with the APO effect greatly contributes to the development of new drugs for AD.