JP6319912B2 - アミロイドβ蛋白質により誘発される認知障害の治療剤およびアルツハイマー病治療薬、ならびにこれらに関連する治療方法および病態解析方法 - Google Patents
アミロイドβ蛋白質により誘発される認知障害の治療剤およびアルツハイマー病治療薬、ならびにこれらに関連する治療方法および病態解析方法 Download PDFInfo
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Description
VLSSQQFLHRGHQPPPEMAGHSLASSHRNSMIPS
AAT (配列番号1)
(II)配列番号1で表されるアミノ酸配列に対して1〜3個のアミノ酸が、欠失、付加、置換または側鎖の修飾のいずれか一種以上により改変されたアミノ酸配列からなるペプチド。
HRGHQPPPEMA (配列番号2)
(IV)配列番号2で表されるアミノ酸配列を含む、配列番号1で表されるアミノ酸配列の部分配列に対して、1〜2個のアミノ酸が、欠失、付加、置換または側鎖の修飾のいずれか一種以上により改変されたアミノ酸配列からなるペプチド。
本発明に係るアミロイドβ蛋白質により誘発される認知障害の治療剤は、下記第1〜第6実施形態を包含する。
VLSSQQFLHRGHQPPPEMAGHSLASSHRNSMIPS
AAT (配列番号1)
第2実施形態では、配列番号1で表されるアミノ酸配列に対して1〜3個のアミノ酸が、欠失、付加、置換または側鎖の修飾(非天然アミノ酸、翻訳後修飾アミノ酸などに相当)のいずれか一種以上により改変されたアミノ酸配列からなるペプチドを、本発明の治療剤の有効成分として用いる。欠失は、配列番号1で表されるアミノ酸配列のN末端および/またはC末端における欠失だけでなく、配列番号1で表されるアミノ酸配列の内部での欠失も包含する。付加は、配列番号1で表されるアミノ酸配列のN末端および/またはC末端への付加だけでなく、配列番号1で表されるアミノ酸配列の内部への付加、すなわち挿入も包含する。第2実施形態において、改変されるアミノ酸の数は通常1〜3個であるが、好ましくは1または2個、より好ましくは1個である。欠失、付加、置換または側鎖の修飾のうち二種以上の組み合わせによってアミノ酸配列が改変されている場合、前記個数はそれらの合計の個数を表す。このような第2実施形態における欠失、付加(挿入)、置換または側鎖の修飾は、本発明の作用効果を阻害しない限り、配列番号1で表されるアミノ酸配列に含まれる配列番号2で表されるアミノ酸配列の部分(HRGHQPPPEMA)においてなされていてもよいし、配列番号2で表されるアミノ酸配列以外の部分においてなされていてもよい。
HRGHQPPPEMA (配列番号2)
ここで、部分配列とは、配列番号1で表されるアミノ酸配列のうちの連続する一部のアミノ酸配列であり(つまり配列番号1で表されるアミノ酸配列の全部は「部分配列」の定義には包含されない)、配列番号1で表されるアミノ酸配列からなるペプチドのN末端および/またはC末端側から少なくとも1個のアミノ酸を切除することにより作製することができる。このような部分配列からなるペプチドは、配列番号2で表されるアミノ酸配列のみからなるペプチドであってもよいし、配列番号2で表されるアミノ酸配列のN末端および/またはC末端に、配列番号1と同様のアミノ酸配列が付加されたアミノ酸配列からなるペプチドであってもよい。
本発明に係るアルツハイマー病治療薬は、上述したような本発明に係る治療剤を含有し、さらに任意で、本発明の治療剤(所定のペプチド)以外の有効成分、剤形に応じた製薬学的に許容される担体、その他一般的な医薬品に用いられている製薬学的添加物などを含有していてもよい。すなわち、本発明に係るアルツハイマー病治療薬は、そのような成分を含有する医薬組成物として調製することができる。
上述したような治療剤は、アミロイドβ蛋白質により誘発される認知障害を治療するために使用することができる。また、上述したような治療薬は、アルツハイマー病を治療するために使用することができる。
本発明における所定のペプチド、すなわち前述したような第1〜第6実施形態において用いられるペプチドは、アミロイドβ蛋白質により誘発される認知障害またはアルツハイマー病の病態解析方法において使用することもできる。すなわち、本発明に係るアミロイドβ蛋白質により誘発される認知障害の病態解析方法は、本発明で用いられる所定のペプチドを、アミロイドβ蛋白質により誘発される認知障害を発症した哺乳類(ヒトまたはヒト以外の哺乳類)またはそのモデル動物(ヒト以外の哺乳類)に投与するステップ、あるいはそのモデル細胞としての培養神経細胞または神経細胞に発現している生体分子に添加するステップを含む。また、本発明に係るアルツハイマー病の病態解析方法は、本発明で用いられる所定のペプチドを、アルツハイマー病に罹患した哺乳類(ヒトまたはヒト以外の哺乳類)またはそのモデル動物(ヒト以外の哺乳類)に投与するステップ、あるいはそのモデル細胞としての培養神経細胞または神経細胞に発現している生体分子に添加するステップを含む。
アミロイドβ蛋白質オリゴマー体投与による記憶障害マウスモデルの作製、および新規物体認識試験 (novel object recognition test) による記憶獲得能力の評価は、過去の論文に従っておこなった (Balducci et al, Proc Natl Acad Sci USA 107, 2295-2300, 2010)。
amyloid-β42:DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA
p3-Alcβ37: VLSSQQFLHRGHQPPPEMAGHSLASSHRNSMIPSAAT
p3-Alcβ[1-19]: VLSSQQFLHRGHQPPPEMA
p3-Alcβ[20-37]: GHSLASSHRNSMIPSAAT
p3-Alcβ[1-11]: VLSSQQFLHRG
p3-Alcβ[9-19]: HRGHQPPPEMA
加えて、使用したペプチドはそれぞれ以下から入手した: amyloid-β42 (Keck Biotechnology Resource Laboratory, Yale University), p3-Alcβ37 (Keck Biotechnology Resource Laboratory, Yale University), p3-Alcβ[1-19] (Genemed Synthesis, and Peptide Institute), p3-Alcβ[20-37] (Genemed Synthesis, and Peptide Institute), p3-Alcβ[1-11] (Peptide Institute), p3-Alcβ[9-19] (Peptide Institute)。
人工脳脊髄液を投与したマウスでは、既知物体Aの探索時間より、新規物体Bの探索時間が有意に長かった (図1A, n = 11 mice, P < 0.01, paired t-test)。すなわち、正常に記憶が獲得されていた。一方で、アミロイドβ蛋白質オリゴマー体を投与したマウスでは、既知物体Aと新規物体Bの探索時間がほぼ同じであった (図1B,n = 20 mice, P > 0.05, paired t-test)。すなわち、記憶獲得が完全に障害されているのが分かった。さらに我々は、アミロイドβ蛋白質オリゴマー体に加えてp3-Alcβ37ペプチドを混合投与したマウスでは、記憶能力が顕著に回復していることを見出した (図1C,n = 14 mice, P < 0.01, paired t-test)。図2では、識別指標を用いて各グループの記憶獲得能力を表わしている。人工脳脊髄液投与群と比較してオリゴマー体投与群では、識別指標の有意な低下が観察された (図2,P < 0.01, Tukey test)。オリゴマー体投与群と比較してオリゴマー体/p3-Alcβ37混合液投与群では、識別指標の有意な上昇が観察された (図2,P < 0.01, Tukey test)。さらに、人工脳脊髄液投与群とオリゴマー体/p3-Alcβ37投与群では、識別指標の有意な差は見られなかった (図2,P > 0.05, Tukey test)。これらの結果は、アミロイドβ蛋白質オリゴマー体により誘発される記憶障害は、p3-Alcβ37ペプチドの脳内投与により劇的に改善されることを示している。
配列番号2:p3-Alcβ[9-19] / a part of p3-Alc beta 37 (position 9-19)
配列番号3:p3-Alcβ[1-11] / a part of p3-Alc beta 37 (position 1-11)
配列番号4:p3-Alcβ[1-19] / a part of p3-Alc beta 37 (position 1-19)
配列番号5:p3-Alcβ[20-37] / a part of p3-Alc beta 37 (position 20-37)
配列番号6:amyloid-β42
Claims (6)
- 下記(I)、(III)または(V)のいずれかに該当するペプチドを有効成分として含有することを特徴とする、アミロイドβ蛋白質により誘発される認知障害の治療剤。
(I)配列番号1で表されるアミノ酸配列からなるペプチド。
VLSSQQFLHRGHQPPPEMAGHSLASSHRNSMIPSAAT
(配列番号1)
(III)配列番号2で表されるアミノ酸配列を含む、配列番号1で表されるアミノ酸配列の部分配列からなるペプチド。
HRGHQPPPEMA (配列番号2)
(V)配列番号2で表されるアミノ酸配列を含み、当該アミノ酸配列のN末端および/またはC末端に合計で1〜50個のアミノ酸が付加されたアミノ酸配列(ただし、配列番号1で表されるアミノ酸配列の全部または一部と一致する場合を除く。)からなるペプチド。 - 請求項1に記載の治療剤を含有する、アルツハイマー病治療薬。
- 請求項1に記載の治療剤を、アミロイドβ蛋白質により誘発される認知障害を発症した哺乳類(ヒトを除く)またはそのモデル動物に投与するステップを含むことを特徴とする、アミロイドβ蛋白質により誘発される認知障害の治療方法。
- 請求項2に記載の治療薬を、アルツハイマー病に罹患した哺乳類(ヒトを除く)またはそのモデル動物に投与するステップを含むことを特徴とする、アルツハイマー病の治療方法。
- 前記(I)、(III)または(V)のいずれかに該当するペプチドを、アミロイドβ蛋白質により誘発される認知障害を発症した哺乳類(ヒトを除く)またはそのモデル動物に投与するステップ、あるいはそのモデル細胞としての培養神経細胞または神経細胞に発現している生体分子に添加するステップを含むことを特徴とする、アミロイドβ蛋白質により誘発される認知障害の病態解析方法。
- 前記(I)、(III)または(V)のいずれかに該当するペプチドを、アルツハイマー病に罹患した哺乳類(ヒトを除く)またはそのモデル動物に投与するステップ、あるいはそのモデル細胞としての培養神経細胞または神経細胞に発現している生体分子に添加するステップを含むことを特徴とする、アルツハイマー病の病態解析方法。
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