Familial forms of Alzheimer's disease (FAD) are caused by mutations in the gene encoding amyloid precursor protein, whose processing can result in formation of β-amyloid (Aβ). FAD can also result from mutations in the presenilin 1/2 (PSEN1/2) genes, whose protein products partially compose the γ-secretase complex that cleaves Aβ from amyloid precursor protein fragments. Psen1 KO mice and knock-in (KI) mice with homozygous FAD-associated L435F mutations (Psen1LF/LF ) are embryonic and perinatally lethal, precluding a more rigorous examination of the effect of Alzheimer's disease-causing Psen1 mutations on neurodegeneration. Given that the rat is a more suitable model organism with regard to surgical interventions and behavioral testing, we generated a rat KI model of the Psen1LF mutation. In this study, we focused on young Psen1LF rats to determine potential early pathogenic changes caused by this mutation. We found that, unlike Psen1LF/LF mice, Psen1LF/LF rats survive into adulthood despite loss of γ-secretase activity. Consistent with loss of γ-secretase function, Psen1LF/LF rats exhibited low levels of Aβ38, Aβ40, and Aβ42 peptides. In contrast, levels of Aβ43, a longer and potentially more amyloidogenic Aβ form, were significantly increased in Psen1LF/LF and Psen1LF/w rats. The longer survival of these KI rats affords the opportunity to examine the effect of homozygous Psen1 Alzheimer's disease-associated mutations on neurodegeneration in older animals.

中文翻译：

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具有纯合 PSEN1L435F 阿尔茨海默突变的敲入大鼠可存活，并表现出选择性 γ-分泌酶活性丧失，导致低 Aβ40/42 和高 Aβ43。


家族性阿尔茨海默病 (FAD) 是由编码淀粉样前体蛋白的基因突变引起的，该蛋白的加工可导致 β-淀粉样蛋白 (Aβ) 的形成。 FAD 也可能由早老素 1/2 (PSEN1/2) 基因突变引起，该基因的蛋白质产物部分组成了 γ-分泌酶复合物，可将 Aβ 从淀粉样蛋白前体蛋白片段中裂解出来。具有纯合 FAD 相关 L435F 突变 (Psen1LF/LF ) 的 Psen1 KO 小鼠和敲入 (KI) 小鼠在胚胎和围产期是致命的，因此无法对引起阿尔茨海默氏病的 Psen1 突变对神经退行性疾病的影响进行更严格的检查。鉴于大鼠是更适合手术干预和行为测试的模型生物，我们构建了 Psen1LF 突变的大鼠 KI 模型。在这项研究中，我们重点关注年轻的 Psen1LF 大鼠，以确定这种突变引起的潜在早期致病变化。我们发现，与 Psen1LF/LF 小鼠不同，尽管 γ-分泌酶活性丧失，Psen1LF/LF 大鼠仍能存活至成年期。与 γ 分泌酶功能丧失一致，Psen1LF/LF 大鼠表现出低水平的 Aβ38、Aβ40 和 Aβ42 肽。相比之下，Psen1LF/LF 和 Psen1LF/w 大鼠中 Aβ43（一种更长且可能更容易产生淀粉样变的 Aβ 形式）的水平显着增加。这些 KI 大鼠的存活时间较长，为研究纯合 Psen1 阿尔茨海默病相关突变对老年动物神经退行性疾病的影响提供了机会。