ウエタ　ヨシフミ   UETA Yoshifumi   植田　禎史    所属   医学部 医学科    職種   講師
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Suppression of a neocortical potassium channel activity by intracellular amyloid-β and its rescue with Homer1a.
掲載誌名	正式名：The Journal of Neuroscience 略　 称：J Neurosci ISSNコード：1529-2401(Electronic)0270-6474(Linking)
巻・号・頁	31(31),pp.11100-11109
著者・共著者	Yamamoto Kenji†, Ueta Yoshifumi, Wang Li, Yamamoto Ryo, Inoue Naoko, Inokuchi Kaoru, Aiba Atsu, Yonekura Hideto, Kato Nobuo*
担当区分	2nd著者
発行年月	2011/08
概要	It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ(1-40), broadened spike width and augmented Ca(2+) influx via voltage-dependent Ca(2+) channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K(+) (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca(2+) influx was caused by elongated spike duration, but not attributable to direct Ca(2+) channel modulation by Aβ(1-42). The Aβ(1-42)-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ(1-42), which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ(1-42) effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ(1-42) is a possible key mechanism for early dysfunction in the ADbrain, which may be counteracted by activity-dependent expression of Homer1a.
DOI	10.1523/JNEUROSCI.6752-10.2011
文献番号	21813671
PMID	21813671