Apomorphine treatment in Alzheimer mice promoting amyloid-[beta] 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 (APPKM670/671NL/PS1M146V) and a tau gene mutation (TauP301L). 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 [PUBLICATION ABSTRACT]