Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation

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

Research output: Contribution to journalArticle

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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 (APPKM670/671NL/PS1 M146V) 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 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 H2O2 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.

Original languageEnglish
Pages (from-to)248-256
Number of pages9
JournalAnnals of Neurology
Volume69
Issue number2
DOIs
Publication statusPublished - Feb 1 2011

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Apomorphine
Amyloid
Alzheimer Disease
Therapeutics
Oxidative Stress
Insulysin
Serum Amyloid A Protein
Mutation
Heme Oxygenase-1
Dopamine Agonists
Proteasome Endopeptidase Complex
Subcutaneous Injections
Short-Term Memory
Genes
Parkinson Disease
Cultured Cells
Proteins
Cell Culture Techniques
Western Blotting
Staining and Labeling

All Science Journal Classification (ASJC) codes

  • Neurology
  • Clinical Neurology

Cite this

Himeno, E., Ohyagi, Y., Ma, L., Nakamura, N., Miyoshi, K., Sakae, N., ... Kira, J. I. (2011). Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. Annals of Neurology, 69(2), 248-256. https://doi.org/10.1002/ana.22319

Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. / Himeno, Eri; Ohyagi, Yasumasa; Ma, Linqing; Nakamura, Norimichi; Miyoshi, Katsue; Sakae, Nobutaka; Motomura, Kyoko; Soejima, Naoko; Yamasaki, Ryo; Hashimoto, Tetsuya; Tabira, Takeshi; M. Laferla, Frank; Kira, Jun Ichi.

In: Annals of Neurology, Vol. 69, No. 2, 01.02.2011, p. 248-256.

Research output: Contribution to journalArticle

Himeno, E, Ohyagi, Y, Ma, L, Nakamura, N, Miyoshi, K, Sakae, N, Motomura, K, Soejima, N, Yamasaki, R, Hashimoto, T, Tabira, T, M. Laferla, F & Kira, JI 2011, 'Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation', Annals of Neurology, vol. 69, no. 2, pp. 248-256. https://doi.org/10.1002/ana.22319
Himeno E, Ohyagi Y, Ma L, Nakamura N, Miyoshi K, Sakae N et al. Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. Annals of Neurology. 2011 Feb 1;69(2):248-256. https://doi.org/10.1002/ana.22319
Himeno, Eri ; Ohyagi, Yasumasa ; Ma, Linqing ; Nakamura, Norimichi ; Miyoshi, Katsue ; Sakae, Nobutaka ; Motomura, Kyoko ; Soejima, Naoko ; Yamasaki, Ryo ; Hashimoto, Tetsuya ; Tabira, Takeshi ; M. Laferla, Frank ; Kira, Jun Ichi. / Apomorphine treatment in Alzheimer mice promoting amyloid-β degradation. In: Annals of Neurology. 2011 ; Vol. 69, No. 2. pp. 248-256.
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