The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer’s disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored. We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL−G−F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background. Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL−G−F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL−G−F/wt). Insoluble Aβ1–40 and Aβ1–42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL−G−F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1. Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

中文翻译：

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少突胶质细胞淀粉样蛋白沉积在阿尔茨海默病小鼠模型中的贡献


β-淀粉样蛋白 （Aβ） 肽积累成不溶性斑块是阿尔茨海默病 （AD） 的早期病理特征。BACE1 是 Aβ 生成的唯一 β 分泌酶，使其成为 AD 治疗的有吸引力的治疗靶点。虽然 BACE1 抑制剂已被证明可以降低 AD 患者的 Aβ 水平，但由于不需要的突触缺陷，靶向 BACE1 的临床试验失败了。了解 BACE1 在单个细胞类型中的生理作用对于开发用于治疗 AD 的有效 BACE 抑制剂至关重要。最近的单细胞 RNA 转录组学分析显示，少突胶质细胞富含产生 Aβ 所需的基因。然而，少突胶质细胞对 AD 中淀粉样斑块负荷的贡献以及少突胶质细胞特异性 Bace1 缺失的副作用仍有待探索。我们生成了一个少突胶质细胞特异性 Bace1 敲除模型 （Bace1fl/fl;Olig2-Cre） 使用标准电子显微镜监测髓鞘形成的潜在破坏。监测长时程增强 （LTP） 以测量突触完整性。我们穿过了 Bace1fl/fl;具有杂合 AppNL−G-F/wt 敲入 AD 小鼠的 Olig2-Cre 模型生成缺乏少突胶质细胞 Bace1 的 AD 小鼠 （Bace1fl/fl;Olig2-Cre;AppNL-G-F/wt）并检查这些动物的淀粉样斑块数量和不溶性 Aβ 水平和神经胶质增生。进行单核 RNA 测序实验，以检查野生型或 APP 敲入背景下少突胶质细胞响应 Bace1 缺陷的分子变化。少突胶质细胞中的 Bace1 缺失不导致胼胝体髓鞘厚度的变化，但视神经髓鞘厚度略有减少。 通过 LTP 测量的突触强度在 Bace1fl/fl 之间没有差异;Olig2-Cre 和年龄匹配的 Bace1fl/fl 对照动物，表明对突触可塑性没有重大影响。有趣的是，在 12 个月大的杂合 AD 敲入小鼠 （Bace1fl/fl;Olig2-Cre;AppNL−G−F/wt 小鼠）导致海马淀粉样蛋白斑块显著减少 ~ 33%，与年龄匹配的 AD 小鼠 （Bace1fl/fl;AppNL−G−F/wt）。不溶性 Aβ1-40 和 Aβ1-42 水平相对降低，同时在周围的淀粉样斑块中观察到更多的星形胶质细胞和小胶质细胞。无偏性单核 RNA 测序结果显示，APPNL-G-F/wt 敲入小鼠中少突胶质细胞 Bace1 的缺失增加了与 Aβ 生成和清除相关的基因的表达，如 ADAM10、Ano4、ApoE、Il33 和 Sort1。我们的结果提供了令人信服的证据，表明少突胶质细胞中的淀粉样蛋白生成途径有助于 AD 大脑中 Aβ 斑块的形成。虽然特异性靶向少突胶质细胞中的 BACE1 抑制以减少 AD 中的 Aβ 病理可能具有挑战性，但这是未来研究中可能探索的策略。