Development of methods to inhibit apoptosis induced by intracellular amyloid β-protein in Alzheimer's disease

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It is known as "amyloid hypothesis" that extracellular amyloid β-protein (Aβ) is neurotoxic in Alzheimer's disease (AD). While, intraneuronal Aβ accumulation is recently suggested to be neurotoxic. We have found apomorphine sulf ate (APO) to enhance intracellular Aβ degradation. Also, we found that APO protected neurons markedly from oxida tive stress induced by hydrogen peroxide. Furthermore, protective effects of APO were remarkable against oxidative stress and these effects were mediated by elevation of glutathione peroxidase (GPx) activity.We further investigated therapeutic efficacy of APO on an AD mouse model. 3XTg mice, which had two familial AD-related mutant genes (APP-KM670/671NL and PS1-M146V) and a mutation of Tau P301L, demonstrated intrane uronal Aβ accumulation, hyperphosphorylated tau accumulation and memory disturbance at the age of 4 months. Af ter subcutaneous injection of APO at 5 mg/kg once a week until 4 weeks, short-term memory evaluated by Morris water maze test was significantly improved. In pathological study, intraneuronal accumulation of Aβ and hyperphosp horylated tau was very mild in APO-injected mice brain. Accordingly, APO was not only cell protective against oxid ative damage-induced apoptosis but also effective on cognitive dysfunction and pathological change in AD mouse mo del, and proved to be a powerful candidate drug for AD patients.