阿茲海默氏症藥物開發與治療

Drug Development for Azheimer's Disease and its Therapies

胡明寬(Ming-Kuan Hu) ； 廖笳因(Chia-Yin Liao) ； 黃詩雅(Shr-Ya Huang)

《化學》 61卷4期 (2003/12) Pp. 645-653

https://doi.org/10.6623/chem.2003059

摘要

阿茲海默氏症(AD)是一種慢性神經退化疾病，主要癥狀為認知能力喪失、行為偏差與最終死亡。從患者死後腦部分析可觀察到兩處組織學上的異常:類澱粉塊斑與神經糾纏團塊。近幾年，與時劇增的證據支持AD 的類澱粉假說¾類澱粉塊斑是AD 的致病原且並非僅是偶發的。此塊斑的蛋白質成份是一類含39~43 個胺基酸的類澱粉胜(Aβ)，來自於一種功能尚未清楚稱為類澱粉前驅蛋白(APP)的膜蛋白。許多不同的方法用來減少此Aβ，從藥物開發的宏觀來看，直接抑制β-或γ-分泌素是最直接的方式，另一方面，刺激α-分泌素可促使非類澱粉蛋白生成而減少Aβ的產生，β-分泌素已被確定是一種與組基蛋白酵素丁(Cathepsin D)相關的天冬胺酸蛋白，最近以定點突變與親和標識實驗結果認為早老素 (Presenilins, PS)即是γ-分泌素，這些分泌素的確定與純化酵素的分析將是開發有效降低Aβ藥物的關鍵。本篇報導將綜合目前藥物開發與治療策略直接或間接針對減少Aβ含量與降低其具致毒或發炎的沉積物，此策略包括抑制APP 到Aβ的生化過程，主要即對β-或γ-分泌素的抑制與抑制、清除致毒的Aβ沉積物，另外並討論降低膽固醇及Aβ免疫形成的作用。

關鍵字

阿茲海默氏症 ； 類澱粉胜 ； 類澱粉前驅蛋白 ； 分泌素

並列摘要

Alzheimer's disease (AD) is a chronic, neurodegenerative disorder which is characterized by a loss of cognitive ability, behavioral abnormalities, and ultimately death. Post-mortem analysis of the brain of patients discloses two major histological abnormalities: intercellular amyloid plaques and intracellular neurofibrillary tangles. Recent evidence has mounted supporting the amyloid hypothesis of AD, which posits that amyloid plaques are involved in the pathogenesis of AD and are not merely coincident with the disease. The primary component of the plaques is the amyloid-β peptide (Aβ), a 39~43 amino acid peptide derived from the processing of a larger transmembrane protein called amyloid-β precursor protein (APP). A number of different strategies can be pursued to reduce the production of Aβ. From the drug discovery perspective, one straightforward way to achieve this goal is through right inhibition of either β- or γ-secretase. β-secretas has been identified as a novel aspartyl protease related to the cathepsin D. Recently, site-directed mutagenesis and affinity labeling experiments suggest that presenilins areγ-seretase and acitivated through autoproteolysis. The identification of these secretases and the development of purified enzyme assays are critical for realizing effective Aβ lowering agents. This review summarizes current therapeutical strategies directed at lowering Aβ levels and decreasing levels of toxic Aβ aggregates through (1) inhibition of the processing of amyloid precursor protein to Aβ peptide, specifically targeting onβ- orγ-secretase (2) inhibition or clearance of Aβ aggregation, (3) cholesterol reduction, and (4) immunization of Aβ.

並列關鍵字

Alzheimer's disease ； amyloid-β (Aβ) ； Amyloid-βprecursor protein (APP) ； Secretases