Apomorphine treatment in Alzheimer mice promoting amyloid‐β degradation
Identifieur interne : 000394 ( Main/Exploration ); précédent : 000393; suivant : 000395Apomorphine treatment in Alzheimer mice promoting amyloid‐β degradation
Auteurs : Eri Himeno [Japon] ; Yasumasa Ohyagi [Japon] ; Linqing Ma [Japon] ; Norimichi Nakamura [Japon] ; Katsue Miyoshi [Japon] ; Nobutaka Sakae [Japon] ; Kyoko Motomura [Japon] ; Naoko Soejima [Japon] ; Ryo Yamasaki [Japon] ; Tetsuya Hashimoto [Japon] ; Takeshi Tabira [Japon] ; Frank M. Laferla [États-Unis] ; Jun-Ichi Kira [Japon]Source :
- Annals of Neurology [ 0364-5134 ] ; 2011-02.
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/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 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. Ann Neurol 2011
Url:
DOI: 10.1002/ana.22319
Affiliations:
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xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Ohyagi, Yasumasa" sort="Ohyagi, Yasumasa" uniqKey="Ohyagi Y" first="Yasumasa" last="Ohyagi">Yasumasa Ohyagi</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Ma, Linqing" sort="Ma, Linqing" uniqKey="Ma L" first="Linqing" last="Ma">Linqing Ma</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Nakamura, Norimichi" sort="Nakamura, Norimichi" uniqKey="Nakamura N" first="Norimichi" last="Nakamura">Norimichi Nakamura</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Miyoshi, Katsue" sort="Miyoshi, Katsue" uniqKey="Miyoshi K" first="Katsue" last="Miyoshi">Katsue Miyoshi</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Sakae, Nobutaka" sort="Sakae, Nobutaka" uniqKey="Sakae N" first="Nobutaka" last="Sakae">Nobutaka Sakae</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Motomura, Kyoko" sort="Motomura, Kyoko" uniqKey="Motomura K" first="Kyoko" last="Motomura">Kyoko Motomura</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Soejima, Naoko" sort="Soejima, Naoko" uniqKey="Soejima N" first="Naoko" last="Soejima">Naoko Soejima</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Yamasaki, Ryo" sort="Yamasaki, Ryo" uniqKey="Yamasaki R" first="Ryo" last="Yamasaki">Ryo Yamasaki</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Hashimoto, Tetsuya" sort="Hashimoto, Tetsuya" uniqKey="Hashimoto T" first="Tetsuya" last="Hashimoto">Tetsuya Hashimoto</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka</wicri:regionArea><wicri:noRegion>Fukuoka</wicri:noRegion></affiliation></author><author><name sortKey="Tabira, Takeshi" sort="Tabira, Takeshi" uniqKey="Tabira T" first="Takeshi" last="Tabira">Takeshi Tabira</name><affiliation wicri:level="3"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Diagnosis, Prevention, and Treatment of Dementia, Graduate School of Juntendo University, Tokyo</wicri:regionArea><placeName><settlement type="city">Tokyo</settlement></placeName></affiliation></author><author><name sortKey="M Laferla, Frank" sort="M Laferla, Frank" uniqKey="M Laferla F" first="Frank" last="M. 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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 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. Ann Neurol 2011</div></front></TEI><affiliations><list><country><li>Japon</li><li>États-Unis</li></country><region><li>Californie</li></region><settlement><li>Tokyo</li></settlement></list><tree><country name="Japon"><noRegion><name sortKey="Himeno, Eri" sort="Himeno, Eri" uniqKey="Himeno E" first="Eri" last="Himeno">Eri Himeno</name></noRegion><name sortKey="Hashimoto, Tetsuya" sort="Hashimoto, Tetsuya" uniqKey="Hashimoto T" first="Tetsuya" last="Hashimoto">Tetsuya Hashimoto</name><name sortKey="Kira, Jun Chi" sort="Kira, Jun Chi" uniqKey="Kira J" first="Jun-Ichi" last="Kira">Jun-Ichi Kira</name><name sortKey="Ma, Linqing" sort="Ma, Linqing" uniqKey="Ma L" first="Linqing" last="Ma">Linqing Ma</name><name sortKey="Miyoshi, Katsue" sort="Miyoshi, Katsue" uniqKey="Miyoshi K" first="Katsue" last="Miyoshi">Katsue Miyoshi</name><name sortKey="Motomura, Kyoko" sort="Motomura, Kyoko" uniqKey="Motomura K" first="Kyoko" last="Motomura">Kyoko Motomura</name><name sortKey="Nakamura, Norimichi" sort="Nakamura, Norimichi" uniqKey="Nakamura N" first="Norimichi" last="Nakamura">Norimichi Nakamura</name><name sortKey="Ohyagi, Yasumasa" sort="Ohyagi, Yasumasa" uniqKey="Ohyagi Y" first="Yasumasa" last="Ohyagi">Yasumasa Ohyagi</name><name sortKey="Sakae, Nobutaka" sort="Sakae, Nobutaka" uniqKey="Sakae N" first="Nobutaka" last="Sakae">Nobutaka Sakae</name><name sortKey="Soejima, Naoko" sort="Soejima, Naoko" uniqKey="Soejima N" first="Naoko" last="Soejima">Naoko Soejima</name><name sortKey="Tabira, Takeshi" sort="Tabira, Takeshi" uniqKey="Tabira T" first="Takeshi" last="Tabira">Takeshi Tabira</name><name sortKey="Yamasaki, Ryo" sort="Yamasaki, Ryo" uniqKey="Yamasaki R" first="Ryo" last="Yamasaki">Ryo Yamasaki</name></country><country name="États-Unis"><region name="Californie"><name sortKey="M Laferla, Frank" sort="M Laferla, Frank" uniqKey="M Laferla F" first="Frank" last="M. Laferla">Frank M. Laferla</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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