JP6353110B2 - タウ凝集阻害剤 - Google Patents
タウ凝集阻害剤 Download PDFInfo
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- JP6353110B2 JP6353110B2 JP2017075939A JP2017075939A JP6353110B2 JP 6353110 B2 JP6353110 B2 JP 6353110B2 JP 2017075939 A JP2017075939 A JP 2017075939A JP 2017075939 A JP2017075939 A JP 2017075939A JP 6353110 B2 JP6353110 B2 JP 6353110B2
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- Prior art keywords
- tau
- isoprenaline
- shows
- aggregation
- insoluble
- Prior art date
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
タウと結合できる化合物を検索した。10μMの2N4Rタウ(タウ−441 ヒューマン)と10μMのヘパリンとを混合し、37℃でインキュベートし、タウを凝集させた。この凝集したタウサンプル(1ml)をショ糖密度勾配溶液(20%, 30%, 40%, 50%を1mlずつ重層)にロードし、遠心した(200000xg, 2h, 20℃)。その後、上層から1mlずつ溶液を回収し、フラクション(Fr)1-5のサンプルとした。また、ペレットはHEPES溶液に懸濁し、Fr6とした。その後、Fr1,3,5に含まれるタウと所定の6600の化合物との結合能を表面プラズモン共鳴法で解析した。表面プラズモン共鳴法とは、薄金膜上に固定した分子の重さの変化等によって生じる屈折率の変化をモニターすることにより、2種類の物質の分子間相互作用を解析する手法である。表面プラズモン共鳴法は、市販の表面プラズモン共鳴装置、例えばBIAcore2000 (Pharmacia Biosensor社製)によって行うことが可能である。その結果、6600の化合物のうち、111個の化合物がタウと結合することを見出した。
次に、(R)-(-)-エピネフリン及びピロカテコールバイオレットの類似構造体が、タウ凝集を抑制するかどうかをチオフラビンT染色法により解析した。その結果、図1に示されるように、レボドパ、ドーパミン、ノルエピネフリン、及びイソプレナリンは、(R)-(-)-エピネフリンと同様に、チオフラビンT活性を顕著に減少させた。ここで、図1(a)は(R)-(-)-エピネフリン、図1(b)はレボドパ、図1(c)はドーパミン、図1(d)はノルエピネフリン、図1(e)はイソプレナリンによるチオフラビンT活性の変化を示している。
次に、イソプレナリンが培養細胞において、タウ凝集を抑制するかどうかを検討した。細胞はヒトのP301L変異体タウ(タウアイソフォームの301番目のプロリンがロイシンに変異したタウ)をステーブルに発現したNeuro2a cell lineを使用した。これらの細胞にイソプレナリンを0.01、0.1及び1μMの濃度で48時間処置した。その後、SDS-不溶性フラクションを採取し、タウの量の変化を検討した。その結果、図3に示されるように、イソプレナリンは、ポジティブコントロールのGSK3β(グリコーゲン合成酵素キナーゼ3β)阻害剤(GSK3βの機能を物理的又は化学的に阻害する物質を意味する)である塩化リチウムと同様にSDS不溶性タウの量を減少させた。ここで、図3(a)はSDS不溶性フラクションのタウを検出したものであり、図3(b)は図3(a)をグラフ化したものでイソプレナリンはSDS不溶性タウの量を減少させることを示している。
AT8のタウリン酸化はAD病態で観察されるタウの構造変化(MC1抗体で検出可)を誘発することが知られている。そこで、COS-7細胞(アフリカミドリザル腎由来)にWT tauを発現させ、MC1抗体を用いたドットブロット法でタウの構造変化を検出した。ドットブロット法は、タンパク質を電気泳動により分離することなくニトロセルロース膜やPVDF膜に固定し、酵素標識抗体でタンパク質量を特異的に定量する方法である。その結果、図5(a)(b)に示されるように、イソプレナリンはMC1抗体で検出されるタウの構造変化を減少させた。ここで、図5(a)はTBS可溶性フラクションでのMC1抗体陽性タウ、タウリン酸化(AT8サイト)、タウ及びGAPDH(内在性コントロール)を検出したもので、図5(b)はタウに対するMC1抗体陽性タウの比率を示す。また、図5(c)に示されるように、同様の条件において、イソプレナリンはリン酸化も減少させた。ここで、図5(c)はタウに対するリン酸化タウの比率を示す。
イソプレナリンが微小管とタウとの結合にどのような影響を及ぼすかを検討した。WT tauを発現したCOS-7細胞にイソプレナリン10μMを24時間処置後、RA buffer(0.1μM MES, 0.5mM MgSO4, 1mM EGTA, 2mM DTT, 0.1% TritonX-100, 20μM taxol, 2mM GTP)でホモジナイズした。3000xgにて25℃で5分間遠心分離後、トータルフラクションとして上清を採取した。このトータルフラクションを更に100000xgにて20℃で20分間遠心分離し、ペレット(微小管フラクション)を採取した。このようにしてWT tauを発現したCOS-7細胞から微小管フラクションを採取し、タウと微小管安定化の指標であるアセチル化チューブリンを検出した。
次に、イソプレナリンがマウスにおいて、タウ凝集を抑制するかどうかを検討した。P301L tau Tgマウスに粉餌に混合したイソプレナリン(1.5mg/g fed)を3か月間摂取させた。その後、マウスから大脳皮質及び海馬を採取し、−80℃に保存した。これら動物組織から可溶性タウ及び不溶性タウを含む画分を得るため、まず、凍結組織にTBS溶液を加え、ホモジナイズした後に遠心し(23000rpm, 15min, 4℃)、上清とペレットに分けた。その内、上清をTBS可溶性フラクション(可溶性タウを含む)とした。また、ペレットに0.32M スクロースを加え、再度ホモジナイズした後に遠心し(23000rpm, 15min, 4℃)、上清(タウ凝集体を含む)とペレット(核を含む)に分けた。その後、上清に界面活性化剤(1%サルコシル)を加え、インキュベーションし(37℃, 1h)、遠心した(200000xg , 1h, 4℃)。ペレットをレムリバッファー(2-メルカプトエタノール入り)で溶解したものをサルコシル不溶性フラクションとした。TBS可溶性フラクション及びサルコシル不溶性フラクションにおけるタウをSDS-PAGEウェスタンブロット法で検出した。その結果、図7に示されるように、イソプレナリンはP301L tau Tgマウスの脳内におけるサルコシル不溶性タウの量を減少させた。ここで、図7(a)はサルコシル不溶性フラクションのタウを検出したもので、図7(b)は図7(a)を定量・グラフ化したものである。NtgはNon-transgenic mouseを意味する。
P301L tau Tgマウスの脳内では、タウ凝集の進展に伴って、神経細胞数が低下する。このため、タウ凝集抑制作用を有するイソプレナリンはこの神経細胞数の低下を改善できる可能性がある。そこで、イソプレナリンを処置したマウスから脳スライスを作製し、神経細胞数をカウントした。その測定方法として、図8(a)に示されるような0.1ミリ平方メートルのボックスを嗅内皮質(entorhinal cortex)または側頭領域(temporal area)に描き、その中の細胞数をカウントし、平均化したものを1スライスの値とした。スライスは1個体から2枚作製し、その結果、図8(b)及び図8(c)に示されるように、イソプレナリンはP301L tau Tgマウスが示すentoehinal cortex及びtemporal areaにおける細胞数の低下を抑制した。従って、イソプレナリンはタウ凝集を抑制することで、神経細胞数の低下を改善できる可能性が示唆された。なお、図8(b)及び図8(c)において、Miceは使用したマウス数であり、Sliceは細胞数を測定した1個体あたりのスライスの数である。
WT tau Tgマウスから採取したTBS可溶性フラクションにおけるタウリン酸化の変化を検討した。その結果、図9に示されるように、イソプレナリンはモノクローナル抗体tau1で認識するタウの脱リン酸化を増加させた。ここで、図9(a)はTBS可溶性フラクションであり、図9(b)はタウに対する脱リン酸化タウの比率である。このため、マウスにおいてもイソプレナリンはタウ凝集及びタウのリン酸化を抑制することが示唆された。
タウ(10μM)、d-及びd/l-イソプレナリン(1〜100μM)とチオフラビンTを混合した。その後、ヘパリンを加え、37℃でインキュベーションし、タウを凝集させた。また、図中に示した時間において、インキュベーションサンプル中のチオフラビンT活性を測定し、化合物によるタウ凝集抑制作用を検討した。図10(a)はd-イソプレナリン、図10(b)はd/l-イソプレナリンがチオフラビンT活性に及ぼす影響を検討した図である。図10(a)(b)に示されるように、d-イソプレナリンは、d/l-イソプレナリンとほぼ同様のチオフラビンT活性抑制作用を示した。
Claims (1)
- ドーパミン若しくはレボドパであるカテコール構造含有化合物又はその塩を含む、タウオパチーの予防及び/又は治療に用いられるタウ凝集阻害剤。
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MX2019013589A (es) * | 2017-05-16 | 2020-07-20 | Claudio Soto Jara | Deteccion de proteina tau con plegamiento incorrecto. |
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