Steiner H, Capell A, Leimer U, Haass C
Adolf-Butenandt-Institute, Ludwig-Maximilians-University, Dept. of Biochemistry, Munich, Germany.
Eur Arch Psychiatry Clin Neurosci. 1999;249(6):266-70. doi: 10.1007/s004060050098.
Alzheimer's disease is characterized by the invariable accumulation of senile plaques that are predominantly composed of amyloid beta-peptide (Abeta). Abeta is generated by proteolytic processing of the beta-amyloid precursor protein (betaAPP) involving the combined action of beta- and gamma-secretase. Cleavage within the Abeta domain by alpha-secretase prevents Abeta generation. In some very rare cases of familial AD (FAD), mutations have been identified within the betaAPP gene. These mutations are located close to or at the cleavage sites of the secretases and pathologically effect betaAPP processing by increasing Abeta production, specifically its highly amyloidogenic 42 amino acid variant (Abeta42). Most of the mutations associated with FAD have been identified in the two presenilin (PS) genes, particularly the PS1 gene. Like the mutations identified within the betaAPP gene, mutations in PS1 and PS2 cause the increased generation of Abeta42. PS1 has been shown to be functionally involved in Notch signaling, a key process in cellular differentation, and in betaAPP processing. A gene knock out of PS1 in mice leads to an embryonic lethal phenotype similar to that of mice lacking Notch. In addition, absence of PS1 results in reduced gamma-secretase cleavage and leads to an accumulation of betaAPP C-terminal fragments and decreased amounts of Abeta. Recent work may suggest that PS1 could be the gamma-secretase itself, exhibiting the properties of a novel aspartyl protease. Mutagenesis of either of two highly conserved intramembraneous aspartate residues of PS1 leads to reduced Abeta production as observed in the PS1 knockout. A corresponding mutation in PS2 interfered with betaAPP processing and Notch signaling suggesting a functional redundancy of both presenilins. In this issue, some of the recent work on the molecular mechanisms involved in Alzheimer's disease (AD) as well as novel diagnostic approaches and risk factors for AD will be discussed. In the first article, we like to give an overview on mechanisms involved in the proteolytic generation of Amyloid beta-peptide (Abeta), the major pathological player of this devastating disease. In the second part of this article recent results will be described, which demonstrate an unexpected biological and pathological function of an AD associated gene.
阿尔茨海默病的特征是老年斑不断积累，这些老年斑主要由β淀粉样肽（Aβ）组成。Aβ是由β淀粉样前体蛋白（βAPP）经蛋白水解加工产生的，涉及β分泌酶和γ分泌酶的联合作用。α分泌酶在Aβ结构域内的切割可阻止Aβ的产生。在一些非常罕见的家族性阿尔茨海默病（FAD）病例中，已在βAPP基因中发现了突变。这些突变位于分泌酶的切割位点附近或切割位点处，通过增加Aβ的产生，特别是其高度淀粉样生成的42个氨基酸变体（Aβ42），在病理上影响βAPP的加工。与FAD相关的大多数突变已在两个早老素（PS）基因中被发现，特别是PS1基因。与在βAPP基因中发现的突变一样，PS1和PS2中的突变会导致Aβ42产生增加。已证明PS1在Notch信号传导中发挥功能作用，Notch信号传导是细胞分化中的一个关键过程，并且在βAPP加工中也发挥作用。在小鼠中敲除PS1基因会导致一种胚胎致死表型，类似于缺乏Notch的小鼠。此外，缺乏PS1会导致γ分泌酶切割减少，并导致βAPP C末端片段积累以及Aβ量减少。最近的研究可能表明PS1可能就是γ分泌酶本身，具有一种新型天冬氨酸蛋白酶的特性。PS1两个高度保守的膜内天冬氨酸残基中的任何一个发生诱变都会导致Aβ产生减少，这与在PS1基因敲除小鼠中观察到的情况相同。PS2中的相应突变会干扰βAPP加工和Notch信号传导，这表明两种早老素在功能上具有冗余性。在本期中，将讨论一些关于阿尔茨海默病（AD）分子机制的最新研究工作以及AD的新型诊断方法和危险因素。在第一篇文章中，我们将概述淀粉样β肽（Aβ）蛋白水解产生的机制，Aβ是这种毁灭性疾病的主要病理因素。在本文的第二部分，将描述最近的研究结果，这些结果证明了一个与AD相关基因意想不到的生物学和病理功能。
