Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation.

Abstract

OBJECTIVE:

Intracellular amyloid β-protein (Aβ) 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 Aβ degradation, activity of Aβ-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 Aβ, hyper-phosphorylated tau (p-tau), p53, and heme oxygenase-1 proteins were observed. Moreover, APO promoted degradation of intracellular Aβ, increased activity of proteasome and insulin-degrading enzyme, protected against H(2) O(2) toxicity, and decreased p53 protein levels in the cultured cells.

INTERPRETATION:

3xTg-AD mice show intraneuronal Aβ accumulation and memory disturbances before extracellular Aβ deposition. Our data demonstrating improvement of memory function of 3xTg-AD mice with decreases in intraneuronal Aβ and p-tau levels by APO treatment strongly suggest that intraneuronal Aβ is an important therapeutic target and APO will be a novel drug for AD.

• Authors: Eri Himeno, Yasumasa Ohyagi, Linqing Ma, Norimichi Nakamura, Katsue Miyoshi, Nobutaka Sakae, Kyoko Motomura, Naoko Soejima, Ryo Yamasaki, Tetsuya Hashimoto, Takeshi Tabira, Frank M LaFerla, Jun-ichi Kira
• Journal: Annals of neurology (Ann Neurol) Vol. 69 Issue 2 Pg. 248-56 (Feb 2011) ISSN: 1531-8249 [Electronic] United States
• PMID: 21387370 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American Neurological Association.

Chemical References

• Amyloid beta-Peptides
• Dopamine Agonists
• tau Proteins
• Neprilysin
• Insulysin
• Proteasome Endopeptidase Complex
• Apomorphine

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Apomorphine (pharmacology, therapeutic use)
• Blotting, Western
• Brain (drug effects, metabolism)
• Cells, Cultured
• Disease Models, Animal
• Dopamine Agonists (pharmacology, therapeutic use)
• Immunohistochemistry
• Insulysin (metabolism)
• Maze Learning (drug effects)
• Memory, Short-Term (drug effects)
• Mice
• Mice, Transgenic
• Neprilysin (metabolism)
• Neurons (drug effects, metabolism)
• Oxidative Stress (drug effects, physiology)
• Phosphorylation (drug effects)
• Proteasome Endopeptidase Complex (metabolism)
• Statistics, Nonparametric
• tau Proteins (metabolism)