Apomorphine Treatment in Alzheimer Mice Promoting Amyloid-β Degradation

Objective: Intracellular amyloid beta-protein (A beta) contributes to neurodegeneration in Alzheimer disease (AD). Apomorphine (APO) is a dopamine receptor agonist for Parkinson disease and also protects against oxidative stress. Efficacy of APO for an AD mouse model and effects of APO on cell cultures are studied. Methods: The triple transgenic AD mouse model (3xTg-AD) has 2 familial AD-related gene mutations (APP(KM670/671NL)/PS1(M146V)) and a tau gene mutation (Tau(P301L)). Six-month-old 3xTg-AD mice were treated with subcutaneous injections of APO once a week for 1 month. Memory function was evaluated by Morris water maze before and after the treatment. Brain tissues were examined by immunohistochemical staining and Western blotting. Effects of APO on intracellular A beta degradation, activity of A beta-degrading enzymes, and protection against oxidative stress were studied in cultured SH-SY5Y cells. Results: After APO treatment, short-term memory function was dramatically improved. Significant decreases in the levels of intraneuronal A beta, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular A beta, increased activity of proteasome and insulin-degrading enzyme, protected against H2O2 toxicity, and decreased p53 protein levels in the cultured cells. Interpretation: 3xTg-AD mice show intraneuronal A beta accumulation and memory disturbances before extracellular A beta deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal A beta and p-tau levels by APO treatment strongly suggest that intraneuronal A beta is an important therapeutic target and APO will be a novel drug for AD. ANN NEUROL 2011;69:248-256