Alzheimer's disease (AD) is characterized by the formation β-amyloid (Aβ) deposited neuritic plaques. Recent evidence suggests that abnormal lipid metabolism and accumulation could serve as biomarkers for neurodegenerative diseases, including AD. Tubular endoplasmic reticulum protein, reticulon 3 (RTN3), plays a crucial role in the development of neuritic plaque and lipid metabolism in AD brains. In present study, we sought to investigate a potential association between neutral lipid accumulation and AD pathology. BODIPY 500/510 dye was used to label neutral lipid surrounding Aβ plaques in APP mouse and AD postmortem brains samples. Immunofluorescent images were captured using confocal microscope and co-localization between lipid metabolism proteins and neutral lipids were evaluated. Lipid accumulation in Aβ plaque surrounding dystrophic neurites (DNs) was observed in the cortical region of AD mouse models and human AD brain samples. The neutral lipid staining was not co-localized with IBA1-labeled microglia or GFAP-labeled astrocytes, but it was co-labeled with VAMP2 and neurofilament. We further showed that neutral lipids were accumulated in RTN3 immunoreactive DNs. Both the neutral lipids accumulation and RIDNs formation showed age-dependent patterns in surrounding amyloid plaques. Mechanistic studies revealed that RTN3 likely contributes to the enrichment of neutral lipids near plaques by interacting with heat shock cognate protein 70 (HSC70) and diminishing its function in chaperone-mediated lipophagy. Our study provides immunohistochemical evidence of neutral lipids being enriched in DNs near amyloid plaques. Our findings shed light on RTN3-mediaed lipid accumulation in AD neuropathology and provide fresh insights into the role of RTN3 in neurodegenerative diseases.

中文翻译：

---

阿尔茨海默病淀粉样蛋白斑周围营养不良的神经突中中性脂质的积累

阿尔茨海默病 (AD) 的特征是形成 β-淀粉样蛋白 (Aβ) 沉积的神经炎斑块。最近的证据表明，异常的脂质代谢和积累可以作为神经退行性疾病（包括 AD）的生物标志物。管状内质网蛋白，即网状蛋白 3 (RTN3)，在 AD 大脑神经炎斑块的形成和脂质代谢中起着至关重要的作用。在本研究中，我们试图探讨中性脂质积累与 AD 病理学之间的潜在关联。BODIPY 500/510 染料用于标记 APP 小鼠和 AD 死后脑样本中 Aβ 斑块周围的中性脂质。使用共聚焦显微镜捕获免疫荧光图像，并评估脂质代谢蛋白和中性脂质之间的共定位。在 AD 小鼠模型和人类 AD 脑样本的皮质区域中观察到营养不良性神经突 (DN) 周围的 Aβ 斑块中存在脂质积累。中性脂质染色不与 IBA1 标记的小胶质细胞或 GFAP 标记的星形胶质细胞共定位，但与 VAMP2 和神经丝共标记。我们进一步表明，中性脂质在 RTN3 免疫反应性 DN 中积累。淀粉样斑块周围的中性脂质积累和 RIDN 形成均显示出年龄依赖性模式。机制研究表明，RTN3 可能通过与热休克同源蛋白 70 (HSC70) 相互作用并削弱其在分子伴侣介导的自噬中的功能，从而有助于斑块附近中性脂质的富集。我们的研究提供了免疫组织化学证据，表明淀粉样斑块附近的 DN 中中性脂质富集。我们的研究结果揭示了 AD 神经病理学中 RTN3 介导的脂质积累，并为 RTN3 在神经退行性疾病中的作用提供了新的见解。