Amyloid beta protein impairs motor function via thromboxane A2 in the rat striatum.
Amyloid beta protein (Abeta) deposits are found in the striatum of patients with Alzheimer disease (AD) showing extrapyramidal motor dysfunction, but neuronal cell loss has not yet been detected. To clarify how Abeta impairs motor function, we analyzed intrastriatally Abeta-injected rats. Unilateral injection of Abeta(25-35) enhanced apomorphine-induced circling in an ipsilateral direction, indicating ipsilateral dysfunction of dopaminergic nigrostriatal pathways. Volumes of lesion in the Abeta(25-35)-injected striata were significantly higher than those in the saline-injected ones. The correlation between lesion volume and circling behavior was close to significance, but slightly too low, suggesting the possible involvement of other factors in the striatal dysfunction. Abeta(25-35) significantly elevated the level of thromboxane A2 (TXA2). A stable TXA2 agonist, U46619, enhanced circling behavior, and TXA2 receptor antagonists attenuated U46619- and Abeta(25-35)-enhanced circling behavior. This study demonstrated that Abeta(25-35) impairs the motor function of dopaminergic neurons via neuronal cell loss and TXA2. It also sheds light on the therapeutic potential of TXA2 receptor blockers for the neurotoxicity of Abeta.
Yagami
Tatsurou
T
Discovery Research Laboratories, Shionogi and Co., Ltd., Fukushima, Osaka 553-0002, Japan. yagami@pharmac.med.yokohama-cu.ac.jp
Takahara
Yukio
Y
Ishibashi
Chiyomi
C
Sakaguchi
Gaku
G
Itoh
Naohiro
N
Ueda
Keiichi
K
Nakazato
Hitoshi
H
Okamura
Noboru
N
Hiramatsu
Yoshiharu
Y
Honma
Tsunetoshi
T
Arimura
Akinori
A
Sakaeda
Toshiyuki
T
Katsuura
Goro
G
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000503:physiopathology*; D018491:Dopamine Agonists / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009046:Motor Neurons / Q000187:drug effects* / Q000502:physiology; D009069:Movement Disorders / Q000473:pathology / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018491:Dopamine Agonists; D010446:Peptide Fragments; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C074636:amyloid beta-protein (25-35); D013928:Thromboxane A2; D001058:Apomorphine