Affiliations: [a] Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| [b] Department of Geriatric Medicine and Neurology, Graduate School of Medicine, Ehime University, Ehime, Japan
| [c] Department of Neurological Therapeutics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence:
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Correspondence to: Yasumasa Ohyagi, Department of Geriatric Medicine and Neurology, Graduate School of Medicine, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan. Tel.: +81 89 960 5851; Fax: +81 89 960 5852; E-mail: ohyagiy@m.ehime-u.ac.jp.
Abstract: Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer’s disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS616 and pS636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS616 and pS636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.
