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βSecretase Akira Tamaoka 1 1Clinical Pathophysiology of the Neurological Disorders, University of Tsukuba School of Medicine Keyword: アルツハイマー病 , アミロイドβ蛋白 , βセクレターゼ , BACE1 , BACE2 , アスパラギン酸プロテアーゼ pp.292-306
Published Date 2005/6/10
DOI https://doi.org/10.11477/mf.1431100047
  • Abstract
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Several lines of evidences suggest that amyloid β protein(Aβ) is crucially important to the pathophysiology of Alzheimer's disease(AD). Senile plaques, primarily composed of Aβ, progressively develop in the brains of AD patients, and mutations in three genes[amyloid precursor protein(APP), presenilin 1(PS1), and presenilin 2(PS2)]cause early onset familial AD(FAD)by increasing toxic Aβ42 peptide, whereas apolipoprotein-ε4, one of the strongest risk factors for AD, enhances Aβ40. Down syndrome patients, who all develop early-onset AD, have an extra copy of the APP gene on chromosome 21 and thus overexpress both Aβ40 and Aβ42. Because of such a strong association between AD and Aβ, therapeutic strategies to decrease the concentration of Aβ in the brain should be beneficial for the treatment of AD.

 Aβ is a proteolytic product of the APP, which is a large TypeⅠ membrane protein. Two proteases, calledβ-andγ-secretase, cleave APP to generate Aβ peptide. Recently, γ-secretase has been tentatively identified as the presenilin complex, whose major components are PS1 and PS2, whileβ-secretase has been shown to be the novel transmembrane aspartic protease,β-site APP Cleaving Enzyme 1(BACE1;also called Asp2 and memapsin2). BACE2, a novel protease homologous to BACE1, was also found, and the two BACE enzymes are considered to belong to a new family of transmembrane aspartic proteases. Since BACE1 shows all the properties of theβ-secretase and BACE1 knock out mice reveal apparently normal phenotype, this key enzyme initiating the formation of Aβ is an attractive drug target for AD.

 First of all, substrate-based peptidomimetic BACE inhibitors were designed using the knowledge of the specificity and kinetics of BACE. These include peptidic hydroxyethylene BACE inhibitor, peptide statine based BACE inhibitors and so on. It is notable that the sizes of the modified inhibitors recently reported are comparable to a number of approved peptidomimetic HIV protease inhibitor drugs. The identification of nonpeptidomimetic inhibitors of BACE1 has also appeared to be challenging. Such inhibitors include minoethyl-substituted tetralins, piperazine-substituted phosphinyl-and phosphorylmethyl succinic acid derivatives, and halogen-substituted niarylnaphthalenes. In addition, strategies targeting BACE mRNA recognition and its down-regulation based on the antisense action of small inhibitory nucleic acids(siNAs)are now noteworthy. These include antisense oligonucleotides, catalytic nucleic acids as well as small interfering RNAs(siRNAs).


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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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