Alzheimer's disease (AD) is a multifactorial disorder driven by abnormal amyloid β-peptide (Aβ) levels. In this study, we investigated the role of presenilin-like signal peptide peptidase-like 2b (SPPL2b) in AD pathophysiology and its potential as a druggable target within the Aβ cascade. Exogenous Aβ42 influenced SPPL2b expression in human cell lines and acute mouse brain slices. SPPL2b and its AD-related substrate BRI2 were evaluated in the brains of knock-in AD mice and human postmortem AD brains. An early high cortical expression of SPPL2b was observed, followed by a downregulation in late AD pathology in mice, correlating with synaptic loss. To understand the consequences of pathophysiological SPPL2b dysregulation, we found that SPPL2b overexpression significantly increased APP cleavage, while genetic deletion reduced APP cleavage and Aβ production. Notably, postmortem AD brains showed higher levels of SPPL2b's BRI2 substrate compared to healthy control samples. These results strongly support the involvement of SPPL2b in AD pathology. The early Aβ-induced upregulation of SPPL2b may enhance Aβ production in a vicious cycle, further aggravating Aβ pathology. Therefore, SPPL2b emerges as a potential anti-Aβ drug target.

中文翻译：

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信号肽肽酶样 2b 调节淀粉样蛋白生成途径并在阿尔茨海默病中表现出 Aβ 依赖性表达

阿尔茨海默病 (AD) 是一种由异常淀粉样蛋白 β-肽 (Aβ) 水平驱动的多因素疾病。在这项研究中，我们研究了早老素样信号肽类肽酶 2b (SPPL2b) 在 AD 病理生理学中的作用及其作为 Aβ 级联中的药物靶点的潜力。外源 Aβ42 影响人类细胞系和急性小鼠脑切片中 SPPL2b 的表达。在敲入 AD 小鼠和人类死后 AD 大脑中对 SPPL2b 及其 AD 相关底物 BRI2 进行了评估。观察到 SPPL2b 的早期皮质高表达，随后在小鼠的晚期 AD 病理学中下调，与突触损失相关。为了了解 SPPL2b 病理生理失调的后果，我们发现 SPPL2b 过度表达显着增加 APP 裂解，而基因缺失则减少 APP 裂解和 Aβ 产生。值得注意的是，与健康对照样本相比，死后 AD 大脑显示出更高水平的 SPPL2b 的 BRI2 底物。这些结果有力地支持了 SPPL2b 参与 AD 病理学。早期 Aβ 诱导的 SPPL2b 上调可能会增强 Aβ 的产生，形成恶性循环，进一步加剧 Aβ 病理。因此，SPPL2b 成为潜在的抗 Aβ 药物靶点。