TY - JOUR
T1 - Apomorphine Therapy for Neuronal Insulin Resistance in a Mouse Model of Alzheimer's Disease
AU - Nakamura, Norimichi
AU - Ohyagi, Yasumasa
AU - Imamura, Tomohiro
AU - Yanagihara, Yuki T.
AU - Iinuma, Kyoko M.
AU - Soejima, Naoko
AU - Murai, Hiroyuki
AU - Yamasaki, Ryo
AU - Kira, Jun Ichi
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (Y.O., 22590936, 26461274), by Japan Science and Technology Agency, and by Kakihara Science and Technology Research Foundation.
Publisher Copyright:
© 2017 - IOS Press and the authors. All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.3233/JAD-160344
DO - 10.3233/JAD-160344
M3 - Article
C2 - 28550243
AN - SCOPUS:85021278392
SN - 1387-2877
VL - 58
SP - 1151
EP - 1161
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 4
ER -
