JP2006051029A - β−アミロイド前駆体タンパク質の細胞プロセッシングをモニターするための方法及び組成物 - Google Patents
β−アミロイド前駆体タンパク質の細胞プロセッシングをモニターするための方法及び組成物 Download PDFInfo
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Abstract
【解決手段】β−アミロイド前駆体タンパク質(βAPP)のプロセッシングのモニターは、β−アミロイドペプチドのアミノ末端でのβAPP の切断に起因する可溶性βAPP フラグメントの分泌を検出することによってなされる。βAPP フラグメントの分泌のインビボモニターリングは、アルツハイマー病及び他のβ−アミロイド関連疾病の診断及び進行についてモニターされ、そして培養された細胞からのそのような分泌のインビトロモニターリングは、β−アミロイド生成のインヒビターを同定するためにモニターされ得る。
【選択図】なし
Description
本発明は、一般的にβ−アミロイド前駆体タンパク質のプロセッシングをモニターするための方法及び組成物に関する。より特定には、本発明は、アルツハイマー病の診断、予測及び治療への応答のモニターのためへの、及びアルツハイマー病の処理のための可能な薬物のスクリーニング及び評価のためへのそのような方法及び組成物の使用に関する。
β−アミロイドペプチド(また、A4,βAP, Aβ又は AβP としても言及される:アメリカ特許第 4,666,829号及びWong (1984)Biochem.Biophys.Res.Commun.120. 1131〜1135を参照のこと) は、β−アミロイド前駆体タンパク質 (βAPP)に由来し、これは 695, 751及び 770個のアミノ酸の異なってスプライスされた形で発現される。Kangなど.(1987) Nature 325: 773〜776; Ponteなど.(1988)Nature 331: 525〜527 ;及び Kitaguchiなど.(1988) Nature 331: 530〜532 を参照のこと。アミロイド前駆体タンパク質の通常のプロセッシングは、トランスメンブランドメイン近くの残基 Lys16とLeu17(Kangなど.(1987) 前記においてAsp597が残基1であるνAP領域について番号を付与されている) との間の部位でタンパク質分解性切断を包含し、β−アミロイドペプチド配列の残る部分を保持する細胞外ドメインの構成的分泌をもたらす (Eschなど.(1990) Science 248:1122〜1124) 。
576 586 596
実 験
材料及び方法
1.抗体及び親和性マトリックスの調製
モノクローナル抗体 6C6を、免疫原としてウサギ血清アルブミンに接合されたβAP残基1−28を含む合成ペプチドを用いて、抗体10D5(Hymanなど.(1992) J.Neuropath.Exp.Neurol. 51:76) と同じ態様で発生せしめ、そしてスクリーンした。10D5及び 6C6の両者は、βAP配列の初めの16個のアミノ酸内のエピトープを認識する。 6C6は免疫沈殿における10D5よりもより効果的であり、そして捕獲抗体として使用された。
胎児ニューロン組織検体を、生後12〜14週目の胎児死骸から得た。脳皮質のサンプルをハンクス液(HBSS) により2度、すすいだ。皮質組織(2〜3g)を、1mgのDNase (Sigma Chemical Co., St,Louis, MO D3427)が添加されている冷 HBSS 10mlに置いた。粉砕された懸濁液を、 210μm及び 130μmの Nitexナイロンスクリーンを通して、 Pulliamなど.(1984) J.Virol.Met. 9:301 により記載されているようにして濾過した。
ヒト 293細胞(ATCC No.CRL−1573) を変性し、 APPを過剰発現せしめた (Selkoeなど.(1988) Proc.Natl.Acad.Sci. USA 85:7341) 。細胞を、使用する前、10cmの皿において半集密性(subconfluency)に増殖せしめた。代謝ラベリング及び免疫沈殿を、Oltersdorfなど.(1989)Nature 341:144 及び (1990) J.Biol.Chem. 265:4492に記載されているようにして実質的に行なった。手短に言及すれば、ラベリングは10cmの皿において行なわれた。細胞をメチオニンを有さない培地で洗浄し、0.5mCiの35S −メチオニンにより補充されたメチオニンを有さない培地2mlにおいて20分間、インキュベートし、完全な培地により洗浄し、完全な培地3mlにおいて2時間、追跡した。
ヒト腎臓 293細胞の6つのウェルトレーにおける二重ウェルを、製造業者(Boehringer Mannheim) により記載されるようにして、 DOTAP介在トランスフェクションを用いて正常なヒトβAPP 又は Swedish変異体βAPP のいづれかを発現するプラスミドベクターにより一般的にトランスフェクトした。40時間後、細胞を、10%ウシ胎児血清を含む、メチオニンを含まない DME中に置き、そして20分後、それらを 200μCi/mlの35S−メチオニンにより35分間ラベル化した。次に、細胞を、10%ウシ胎児血清を含む正常な DME培地中に戻し、そしてさらに 2.5時間インキュベートした。培地を細胞から集め、そして1000×gで15分間、回転せしめ、すべての細胞を除いた。上清液を半分に分け、そして半分を標準方法により抗−5抗体により免疫沈殿した。
第2図:ヒト混合された脳細胞培養物からのならし培地における切断されたβAPP の表示
サンプル1は、培養物からのならし培地であり;サンプル2は 6C6−反応性βAPP を消耗された培地であり;そしてサンプル3は 6C6樹脂から抽出された材料である。パネルAを、βAPP 配列 444−592(Oltersdorfなど.(1989) 前記及び (1990) 前記) に対して生ぜしめられた抗−5抗体によりプローブした。パネルBを、材料及び方法セクションに記載されるように抗92によりプローブした。パネルCを、材料及び方法セクションに記載されるようにβAP残基1−16内のエピトープを認識するモノクローナル抗体10D5によりプローブした。C2及びC3において観察された低分子量バンドは、C1には見出されず、そして 6C6樹脂から誘導され、そして一次抗体には無関係なヤギ−抗−マウス IgGアルカリホスファターゼ接合体により認識される(データは示されていない)。
75才の男性から得られたヒト腰動脈 CSF検体1mlを、10% TCAにより沈殿せしめ、10倍の濃度をもたらし、そして第2図に記載されるようにして処理した(但し、ゲルウェルは4cmのスロットであった)。92抗体を、軽く混合しながら、4℃で10時間、それぞれ約60μMの濃度で、種々の可能性ある競争ペプチドの存在下でTTBS 0.5ml中、 6.7μg/mlに希釈した。次に、抗体を1%ゼラチン/TTBSにおいて8倍に希釈し、その後、 CSF由来の材料のブロットのストリップと共にインキュベートし、そして第2図に記載されているようにして処理した。競争ペプチドは次の通りであった:レーン1、競争ペプチドは添加されなかった;レーン2、GSGLTNIKTEEISEVK;レーン3、 YSGLTNIKTEEISEVKM;レーン4、ISEVKM;レーン5、EISEVKMD;レーン6、 CISEVKM;レーン7、 YISEVKM。MW=分子質量マーカー(キロドルトンで示される)。
抗体:抗−5:レーン3,6,9;6C6(βAPペプチド残基1−16に対して検出された);レーン4,7,10;抗体92(APPアミノ酸591−596 に対する) ;レーン5,8,11;7H5 (APP−KPI に対する):レーン12。細胞:左側のパネル (レーン1及び3−5):APP695により安定してトランスフェクトされた 293細胞;中間のパネル (レーン2及び6−8):APP751により安定してトランスフェクトされた 293細胞;左側のパネル (レーン9−13):ヒト胎児脳培養物。対照:レーン1,2及び13:ウサギ抗マウス IgG抗体。矢印:抗体 6C6及び92により認識される分泌される形の APP間での分子質量差異の例。 SDS−PAGEは5% Laemmliゲル上で行なわれた。MW=分子質量マーカー(キロドルトンにより示される)。
第5図は正常な形及び Swedish形の両者のために二重トランスフェクションからの結果を示す。レーン1−4はα5+であり;レーン5−8は 6C6+であり;そしてレーン9−12は 6C6−,α5+サンプルである。レーン1,2,5,6,9及び10は正常なβAPP からであり、レーン3,4,7,8,11及び12はSwedish βAPP からである。その Swedish変異は、高められた AFT−αAPP の生成をもたらし、そしてレーン11及び12はレーン9及び10よりも一層の ATF−βAPP 材料を含む。
残基1−16内のβAPのエピトープを認識するモノクローナル抗体 6C6を、種々のサンプルからの一定のβAPP フラグメントを免疫消耗するために使用した。モノクローナル抗体 6C6を樹脂(上記のような)に結合し、そして上記のようにして、ヒト胎児脳細胞培養物からのならし培地と共にインキュベートした。第2図、レーンC2に見られるように、この樹脂は細胞培養物のならし培地からのβAB1−6を含むβAPP を効果的に除く。しかしながら、実質的なβAPP 免疫反応性は、βAP領域側のエピトープN末端に対して向けられた抗−5抗体により検出されるように樹脂により捕獲されない。
Claims (43)
- 細胞におけるβ−アミロイド前駆体タンパク質(βAPP)のプロセッシングをモニターするための方法であって、前記細胞から分泌される可溶性βAPP フラグメントを検出することを含んで成り、ここで前記βAPP フラグメントがβ−アミロイドペプチド (βAP)のアミノ末端でのβAPP の切断に起因する方法。
- 前記切断がβAP側の方に向かって連続した5個の残基領域のアミノ末端内で生じる請求の範囲第1項記載の方法。
- 前記切断がメチオニン596 又はリシン595 で生じる請求の範囲第2項記載の方法。
- 前記切断がメチオニン596 で生じる請求の範囲第3項記載の方法。
- 前記切断がロイシン596 で生じる請求の範囲第2項記載の方法。
- 前記βAPP フラグメントが、βAPP からのβ−アミロイドペプチドの切断により暴露された、前記フラグメント上のC−末端残基に特異的に結合する物質への暴露により検出される請求の範囲第1項記載の方法。
- 前記βAPP フラグメントが患者サンプルにおいて検出される請求の範囲第1項記載の方法。
- 前記患者サンプルが脳脊髄液である請求の範囲第7項記載の方法。
- 前記βAPP フラグメントが細胞培養物からのならし培地において検出される請求の範囲第1項記載の方法。
- 生物学的サンプルにおけるβ−アミロイド前駆体タンパク質(βAPP)の分泌されたフラグメントの存在を検出するための方法であって、βAPP からのβ−アミロイドペプチド(βAP)の切断により暴露されている、分泌されたフラグメント上のC末端領域に特異的に結合する物質に前記サンプルを暴露し;そして
前記物質と前記分泌されたフラグメントとの間の結合を検出することを含んで成る方法。 - 前記C末端残基がβAP側の方に向かって連続した5個の残基領域のアミノ末端内に存在する請求の範囲第10項記載の方法。
- 前記C末端残基がメチオニン596 又はリシン595 である請求の範囲第11項記載の方法。
- 前記C末端残基がメチオニン596 である請求の範囲第11項記載の方法。
- 前記C末端残基がロイシン596 である請求の範囲第11項記載の方法。
- 前記サンプルが、βAPP からのβ−アミロイドペプチドの切断により暴露されたC−末端残基に対して特異的な抗体に暴露される請求の範囲第10項記載の方法。
- 前記C末端残基がメチオニンである請求の範囲第15項記載の方法。
- 前記C末端残基がロイシンである請求の範囲第15項記載の方法。
- 前記抗体が、暴露されている残基596 を伴って、βAPP の残基 591〜596 を含んで成るペプチドに対して生ぜしめられている請求の範囲第15項記載の方法。
- 前記生物学的サンプルが患者サンプルである請求の範囲第10項記載の方法。
- 前記患者サンプルが脳脊髄液である請求の範囲第19項記載の方法。
- 前記生物学的サンプルが細胞系からのならし培地である請求の範囲第10項記載の方法。
- 患者におけるβ−アミロイド関連疾病を診断又はモニターするための方法であって、
β−アミロイド前駆体タンパク質(βAPP)の分泌されたフラグメントの量又は割合を患者サンプルにおいて測定し、ここで前記βAPPフラグメントがβ−アミロイドペプチドのアミノ末端でのβ−APPの切断に起因する方法。 - 前記切断がβAP側の方に向かって連続した5個の残基領域のアミノ末端内で生じる請求の範囲第22項記載の方法。
- 前記切断がメチオニン596 、ロイシン596 又はリシン595 で生じる請求の範囲第23項記載の方法。
- 前記切断がメチオニン596 で生じる請求の範囲第24項記載の方法。
- 前記患者サンプルが脳脊髄液である請求の範囲第22項記載の方法。
- 分泌されたフラグメントの測定された量又は割合と正常な患者に特徴的な量とを比較することをさらに含んで成り、ここで高められたβAPP の量又は割合がアルツハイマー病の診断である請求の範囲第26項記載の方法。
- 前記βAPP フラグメントが、β−アミロイドペプチドのアミノ末端での APPの切断により暴露された、前記フラグメント上のC−末端残基に特異的に結合する物質への暴露により測定される請求の範囲第22項記載の方法。
- β−アミロイド生成インヒビターを同定するための方法であって:
β−アミロイド前駆体タンパク質(βAPP)のフラグメントの分泌をもたらす条件下で細胞を培養し、ここで前記βAPP フラグメントがβ−アミロイドペプチドのアミノ末端でのβAPP の切断に起因し;
前記培養された細胞を多くの試験化合物に暴露し;そして
分泌されたβAPP フラグメントの量の変化を引き起こす試験化合物を同定することを含んで成る方法。 - 前記細胞が培養されたヒト胎児脳細胞である請求の範囲第29項記載の方法。
- 前記試験化合物が1nM〜1mMの濃度で暴露される請求の範囲第29項記載の方法。
- 前記試験化合物が小分子を含んで成る請求の範囲第29項記載の方法。
- 前記試験化合物が生物学的ポリマーを含んで成る請求の範囲第29項記載の方法。
- β−アミロイドペプチドのアミノ末端で切断される、β−アミロイド前駆体タンパク質(βAPP)の分泌されたフラグメントに特異的に結合する抗体分子を含んで成る抗体組成物。
- 前記分泌されたフラグメントがβAPP からのβAPのインビボ切断に起因し、C末端メチオニン又はロイシンの暴露をもたらす請求の範囲第34項記載の抗体組成物。
- 前記抗体分子が損なわれていない免疫グロブリンを含んで成る請求の範囲第34項記載の抗体組成物。
- 前記抗体分子が免疫グロブリンフラグメントを含んで成る請求の範囲第34項記載の抗体組成物。
- 前記抗体分子がβAPP の少なくとも残基 591−596 を含んで成るペプチドに対して生ぜしめられる請求の範囲第34項記載の抗体組成物。
- 前記ペプチドに対して生ぜしめられた抗血清を含んで成る請求の範囲第38項記載の抗体組成物。
- 精製され、そして単離された形でのβ−アミロイド前駆体タンパク質(βAPP)の可溶性フラグメントであって、前記フラグメントが損なわれていないβAPP からのβ−アミロイドペプチドの切断に起因するC末端メチオニン又はロイシンを有することを特徴とする可溶性フラグメント。
- 脳脊髄液及び培養された細胞からのならし培地から成る群から選択される天然源から単離される請求の範囲第40項記載の可溶性フラグメント。
- βAPP イソフォーム 695の残基18−596 、βAPP イソフォーム 751の残基18−612 、又はβAPP イソフォーム 770の残基18−671から実質的に成る請求の範囲第41項記載の可溶性フラグメント。
- βAPP イソフォーム 695の残基18−595 、βAPP イソフォーム 751の残基18−611 又はβAPP イソフォーム 770の残基18−670から実質的に成る請求の範囲第42項記載の可溶性フラグメント。
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US5213962A (en) * | 1990-04-24 | 1993-05-25 | The Regents Of The University Of California | Purification, detection and methods of use of protease Nexin-2 |
JPH05506990A (ja) * | 1990-04-24 | 1993-10-14 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | プロテアーゼ ネキシン―2の精製、検出、及び使用方法 |
US5385915A (en) * | 1990-05-16 | 1995-01-31 | The Rockefeller University | Treatment of amyloidosis associated with Alzheimer disease using modulators of protein phosphorylation |
WO1991019810A1 (en) * | 1990-06-15 | 1991-12-26 | California Biotechnology Inc. | Transgenic non-human mammal displaying the amyloid-forming pathology of alzheimer's disease |
WO1992000521A1 (en) * | 1990-06-29 | 1992-01-09 | Case Western Reserve University | Diagnostic and prognostic methods based on soluble derivatives of the beta amyloid protein precursor |
US5200339A (en) * | 1990-08-17 | 1993-04-06 | Abraham Carmela R | Proteases causing abnormal degradation of amyloid β-protein precursor |
BE1003316A5 (fr) * | 1990-11-27 | 1992-02-25 | Will L F & Cie Sa | Anticorps monoclonal utile pour le diagnostic de la maladie d'alzheimer, hybridome secreteur d'un tel anticorps monoclonal et procede pour sa preparation. |
US5441870A (en) * | 1992-04-15 | 1995-08-15 | Athena Neurosciences, Inc. | Methods for monitoring cellular processing of β-amyloid precursor protein |
-
1992
- 1992-10-26 US US07/965,971 patent/US5441870A/en not_active Expired - Lifetime
-
1993
- 1993-03-03 CA CA002118243A patent/CA2118243C/en not_active Expired - Lifetime
- 1993-03-03 WO PCT/US1993/001817 patent/WO1993021526A1/en active IP Right Grant
- 1993-03-03 DE DE69333225T patent/DE69333225T2/de not_active Expired - Lifetime
- 1993-03-03 AT AT93907104T patent/ATE251304T1/de active
- 1993-03-03 EP EP93907104A patent/EP0638172B1/en not_active Expired - Lifetime
- 1993-03-03 JP JP51830393A patent/JP3974168B2/ja not_active Expired - Lifetime
- 1993-03-03 AU AU37827/93A patent/AU688726B2/en not_active Expired
- 1993-03-03 NZ NZ251053A patent/NZ251053A/en not_active IP Right Cessation
- 1993-03-03 DK DK93907104T patent/DK0638172T3/da active
- 1993-03-03 ES ES93907104T patent/ES2206455T3/es not_active Expired - Lifetime
- 1993-03-03 PT PT93907104T patent/PT638172E/pt unknown
-
1994
- 1994-10-14 NO NO19943912A patent/NO320067B1/no not_active IP Right Cessation
- 1994-10-14 FI FI944847A patent/FI111546B/fi not_active IP Right Cessation
-
1995
- 1995-05-12 US US08/440,423 patent/US5721130A/en not_active Expired - Lifetime
-
1997
- 1997-05-01 US US08/846,444 patent/US6018024A/en not_active Expired - Lifetime
-
2005
- 2005-08-08 JP JP2005230075A patent/JP2006051029A/ja active Pending
Also Published As
Publication number | Publication date |
---|---|
AU3782793A (en) | 1993-11-18 |
US5441870A (en) | 1995-08-15 |
NZ251053A (en) | 1996-11-26 |
EP0638172A1 (en) | 1995-02-15 |
EP0638172B1 (en) | 2003-10-01 |
AU688726B2 (en) | 1998-03-19 |
EP0638172A4 (en) | 1997-03-19 |
JPH07506967A (ja) | 1995-08-03 |
ATE251304T1 (de) | 2003-10-15 |
DE69333225T2 (de) | 2004-05-06 |
FI111546B (fi) | 2003-08-15 |
US5721130A (en) | 1998-02-24 |
DE69333225D1 (de) | 2003-11-06 |
CA2118243C (en) | 2009-11-03 |
NO943912D0 (no) | 1994-10-14 |
DK0638172T3 (da) | 2004-02-02 |
CA2118243A1 (en) | 1993-10-28 |
FI944847A (fi) | 1994-10-14 |
NO320067B1 (no) | 2005-10-17 |
ES2206455T3 (es) | 2004-05-16 |
JP3974168B2 (ja) | 2007-09-12 |
PT638172E (pt) | 2004-02-27 |
US6018024A (en) | 2000-01-25 |
FI944847A0 (fi) | 1994-10-14 |
NO943912L (no) | 1994-11-10 |
WO1993021526A1 (en) | 1993-10-28 |
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