Department of Human Biology and Human Genetics, University of Kaiserslautern, 67663, Kaiserslautern, Germany.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Acta Neuropathol Commun. 2023 Jun 1;11(1):87. doi: 10.1186/s40478-023-01577-y.
The amyloid precursor protein (APP) is a key player in Alzheimer`s disease (AD) and the precursor of the Aβ peptide, which is generated by consecutive cleavages of β- and γ-secretases. Familial Alzheimer's disease (FAD) describes a hereditary subgroup of AD that represents a low percentage of AD cases with an early onset of the disease. Different APP FAD mutations are thought to have qualitatively different effects on its proteolytic conversion. However, few studies have explored the pathogenic and putative physiological differences in more detail. Here, we compared different FAD mutations, located at the β- (Swedish), α- (Flemish, Arctic, Iowa) or γ-secretase (Iberian) cleavage sites. We examined heterologous expression of APP WT and FAD mutants in non-neuronal cells and their impact on presynaptic differentiation in contacting axons of co-cultured neurons. To decipher the underlying molecular mechanism, we tested the subcellular localization, the endocytosis rate and the proteolytic processing in detail by immunoprecipitation-mass spectrometry. Interestingly, we found that only the Iberian mutation showed altered synaptogenic function. Furthermore, the APP Iowa mutant shows significantly decreased α-secretase processing which is in line with our results that APP carrying the Iowa mutation was significantly increased in early endosomes. However, most interestingly, immunoprecipitation-mass spectrometry analysis revealed that the amino acid substitutions of APP FAD mutants have a decisive impact on their processing reflected in altered Aβ profiles. Importantly, N-terminally truncated Aβ peptides starting at position 5 were detected preferentially for APP Flemish, Arctic, and Iowa mutants containing amino acid substitutions around the α-secretase cleavage site. The strongest change in the ratio of Aβ40/Aβ42 was observed for the Iberian mutation while APP Swedish showed a substantial increase in Aβ1-17 peptides. Together, our data indicate that familial AD mutations located at the α-, β-, and γ-secretase cleavage sites show considerable differences in the underlying pathogenic mechanisms.
淀粉样前体蛋白（APP）是阿尔茨海默病（AD）的关键因素，也是 Aβ肽的前体，Aβ肽通过β-和 γ-分泌酶的连续切割产生。家族性阿尔茨海默病（FAD）描述了 AD 的一个遗传性亚组，占 AD 病例的低比例，疾病发病较早。不同的 APP FAD 突变被认为对其蛋白水解转化有定性不同的影响。然而，很少有研究更详细地探讨其致病和潜在的生理差异。在这里，我们比较了位于β-（瑞典）、α-（佛兰芒、北极、爱荷华）或γ-分泌酶（伊比利亚）切割位点的不同 FAD 突变。我们在非神经元细胞中检查了 APP WT 和 FAD 突变体的异源表达及其对共培养神经元接触轴突中突触前分化的影响。为了解释潜在的分子机制，我们通过免疫沉淀-质谱法详细测试了亚细胞定位、内吞率和蛋白水解处理。有趣的是，我们发现只有伊比利亚突变显示出改变的突触发生功能。此外，APP 爱荷华突变体的 α-分泌酶处理明显减少，这与我们的结果一致，即携带爱荷华突变的 APP 在早期内体中显著增加。然而，最有趣的是，免疫沉淀-质谱分析表明，APP FAD 突变体的氨基酸取代对其加工有决定性影响，这反映在改变的 Aβ 谱中。重要的是，从位置 5 开始的 N 端截断的 Aβ 肽优先检测到 APP 佛兰芒、北极和爱荷华突变体，这些突变体在 α-分泌酶切割位点周围含有氨基酸取代。伊比利亚突变导致 Aβ40/Aβ42 比值变化最大，而 APP 瑞典则导致 Aβ1-17 肽显著增加。总的来说，我们的数据表明，位于 α-、β-和 γ-分泌酶切割位点的家族性 AD 突变在潜在的致病机制方面存在显著差异。
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