Department of Physiology, UT Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
Laboratory of Molecular Neurodegeneration, Peter the Great St. Petersburg State Polytechnical University, 195251 St. Petersburg, Russia.
Int J Mol Sci. 2023 Jan 20;24(3):2092. doi: 10.3390/ijms24032092.
Proteolytic processing of amyloid precursor protein (APP) plays a critical role in pathogenesis of Azheimer's disease (AD). Sequential cleavage of APP by β- and γ-secretases leads to generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) act as catalytic subunits of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 affect APP proteolysis by γ-secretase and influence levels of generated Aβ40 and Aβ42 peptides. The predominant idea in the field is the "amyloid hypothesis" that states that the resulting increase in Aβ42:Aβ40 ratio leads to "toxic gain of function" due to the accumulation of toxic Aβ42 plaques and oligomers. An alternative hypothesis based on analysis of PS1 conditional knockout mice is that "loss of function" of γ-secretase plays an important role in AD pathogenesis. In the present paper, we propose a mechanistic hypothesis that may potentially reconcile these divergent ideas and observations. We propose that the presence of soluble Aβ peptides in endosomal lumen (and secreted to the extracellular space) is essential for synaptic and neuronal function. Based on structural modeling of Aβ peptides, we concluded that Aβ42 peptides and Aβ40 peptides containing non-amyloidogenic FAD mutations in APP have increased the energy of association with the membranes, resulting in reduced levels of soluble Aβ in endosomal compartments. Analysis of PS1-FAD mutations also revealed that all of these mutations lead to significant reduction in both total levels of Aβ produced and in the Aβ40/Aβ42 ratio, suggesting that the concentration of soluble Aβ in the endosomal compartments is reduced as a result of these mutations. We further reasoned that similar changes in Aβ production may also occur as a result of age-related accumulation of cholesterol and lipid oxidation products in postsynaptic spines. Our analysis more easily reconciled with the "loss of γ-secretase function" hypothesis than with the "toxic gain of Aβ42 function" idea. These results may also explain why inhibitors of β- and γ- secretase failed in clinical trials, as these compounds are also expected to significantly reduce soluble Aβ levels in the endosomal compartments.
淀粉样前体蛋白（APP）的蛋白水解加工在阿尔茨海默病（AD）的发病机制中起着关键作用。β-和γ-分泌酶对 APP 的连续切割导致 Aβ40（非淀粉样生成）和 Aβ42（淀粉样生成）肽的产生。早老素-1（PS1）或早老素-2（PS2）作为 γ-分泌酶的催化亚基发挥作用。APP、PS1 或 PS2 中的多种家族性 AD（FAD）突变通过 γ-分泌酶影响 APP 的蛋白水解，并影响生成的 Aβ40 和 Aβ42 肽的水平。该领域的主要观点是“淀粉样假说”，即由于有毒的 Aβ42 斑块和寡聚物的积累，导致 Aβ42:Aβ40 比值的增加导致“毒性获得功能”。基于 PS1 条件性敲除小鼠的分析的替代假设是，γ-分泌酶的“功能丧失”在 AD 的发病机制中起着重要作用。在本文中，我们提出了一个可能协调这些不同观点和观察结果的机制假设。我们提出，内体腔（并分泌到细胞外空间）中可溶性 Aβ 肽的存在对于突触和神经元功能是必需的。基于 Aβ 肽的结构建模，我们得出结论，APP 中的 Aβ42 肽和含有非淀粉样生成 FAD 突变的 Aβ40 肽与膜的结合能增加，导致内体区室中可溶性 Aβ 的水平降低。对 PS1-FAD 突变的分析还表明，所有这些突变都导致 Aβ 产量的总水平和 Aβ40/Aβ42 比值显著降低，表明由于这些突变，内体区室中可溶性 Aβ 的浓度降低。我们进一步推断，由于突触后棘中胆固醇和脂质氧化产物的年龄相关性积累，Aβ 产生的类似变化也可能发生。与“毒性获得 Aβ42 功能”的想法相比，我们的分析更容易与“γ-分泌酶功能丧失”假说相协调。这些结果也可以解释为什么β-和γ-分泌酶抑制剂在临床试验中失败，因为这些化合物也预计会显著降低内体区室中可溶性 Aβ 的水平。
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