レビュー:アルツハイマー病のバイオマーカーとしてのアミロイドβ・アミロイドβ蛋白前駆体
2010年 01月 30日
Review
Amyloid β and APP as biomarkers for Alzheimer’s disease
Experimental Gerontology, 01/29/10
1. Cardinal features of Alzheimer pathology
2. Alzheimer’s disease causation – what is the evidence for amyloid β as a central molecule in the disease process?
3. Aβ-related proteins as core neurochemical markers of AD
4. Limitations and pitfalls
5. Conclusions and future research directions
アルツハイマ-型痴呆(DAT)脳におけるアミロイド形成には、アミロイドB蛋白前駆体(APP)の異常、特にプロテア-ゼ阻害領域が挿入されたアミロイドB蛋白前駆体(APPI)の関与が示唆されている(*)
APPは,695から770個のアミノ酸からなる1回膜貫通型蛋白でC末端の99番目からAβがコードされている。APPはAβのN末端で切断される分泌型APPと膜に残されたC末端側(CTF)に分けられる。CTFは,さらにAβのC末端側で切断され Aβ1-40,Aβ1-42,Aβ1-43,P3(Aβ17-40,17-42)として代謝される。それぞれの部位で働く酵素は,α-,β-,γ- secretaseと想定されている。PS1ノックアウトマウスでAPP CTFが蓄積していたことは,PS1がAPP CTFのγ-secretaseによる代謝(γ-cleavage)に関わっていることを意味する(http://www.igaku-shoin.co.jp/nwsppr/n1999dir/n2331dir/n2331_05.htm)。
Schematic representation of amyloidogenic APP-processing.
In brain, three major isoforms (APP770, APP751 and APP695) exist due to differential splicing of exon 7 that contains the Kunitz protease inhibitor domain (KPI) and exon 8 that contains the OX2 antigen domain.
BACE1 cleaves APP after residue 671, which causes the secretion of sAPP-β and the retention of a 99 residue C-terminal fragment (CTF).
This fragment can undergo further cleavage by γ-secretase to release 40 or 42 amino acid long Aβ fragments.
Cleavage of CTF by γ-secretase releases the APP intracellular domain (AICD) into the cytoplasm.
Fig. 2. Proposed model of Aβ-induced synaptotoxic effects and synapse elimination in AD. Aβ is released from vesicles in the presynaptic terminal in an activity-dependent manner.
Increased release or defective clearance results in Aβ oligomerization.
Aβ oligomers activate postsynaptic intracellular pathways through a putative Aβ receptor, leading to AMPA and NMDA receptor internalization.
The postsynaptically silent synapse is a prerequisite for the subsequent retraction of the presynaptic terminal and the postsynaptic spine, eventually leading to elimination of the synapse.
by internalmedicine | 2010-01-30 10:12 | 精神・認知