Amyloid beta protein impairs motor function via thromboxane A2 in the rat striatum

• Published in: Neurobiology of disease Vol. 16; no. 3; pp. 481 - 489
• Main Authors: Yagami, Tatsurou, Takahara, Yukio, Ishibashi, Chiyomi, Sakaguchi, Gaku, Itoh, Naohiro, Ueda, Keiichi, Nakazato, Hitoshi, Okamura, Noboru, Hiramatsu, Yoshiharu, Honma, Tsunetoshi, Arimura, Akinori, Sakaeda, Toshiyuki, Katsuura, Goro
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.08.2004
• Subjects: Amyloid beta-Peptides - pharmacology; Amyloid β protein; Animals; Apomorphine - pharmacology; Corpus Striatum - cytology; Corpus Striatum - physiopathology; Dopamine Agonists - pharmacology; Locomotion - drug effects; Male; Motor Neurons - drug effects; Motor Neurons - physiology; Movement Disorders - pathology; Movement Disorders - physiopathology; Peptide Fragments - pharmacology; Rats; Rats, Wistar; Receptors, Thromboxane A2, Prostaglandin H2 - agonists; Receptors, Thromboxane A2, Prostaglandin H2 - antagonists & inhibitors; Thromboxane A2; Thromboxane A2 - metabolism; TXA2 receptor blockers
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2004.04.013

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.