Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA.
Department of Pathology, University of California, San Diego, La Jolla, CA, USA.
Cell Rep. 2023 Aug 29;42(8):112956. doi: 10.1016/j.celrep.2023.112956. Epub 2023 Aug 8.
Alzheimer's disease (AD) is the most prevalent cause of dementia; microglia have been implicated in AD pathogenesis, but their role is still matter of debate. Our study showed that single systemic wild-type (WT) hematopoietic stem and progenitor cell (HSPC) transplantation rescued the AD phenotype in 5xFAD mice and that transplantation may prevent microglia activation. Indeed, complete prevention of memory loss and neurocognitive impairment and decrease of β-amyloid plaques in the hippocampus and cortex were observed in the WT HSPC-transplanted 5xFAD mice compared with untreated 5xFAD mice and with mice transplanted with 5xFAD HSPCs. Neuroinflammation was also significantly reduced. Transcriptomic analysis revealed a significant decrease in gene expression related to "disease-associated microglia" in the cortex and "neurodegeneration-associated endothelial cells" in the hippocampus of the WT HSPC-transplanted 5xFAD mice compared with diseased controls. This work shows that HSPC transplant has the potential to prevent AD-associated complications and represents a promising therapeutic avenue for this disease.
阿尔茨海默病（AD）是最常见的痴呆症病因；小胶质细胞被认为与 AD 的发病机制有关，但它们的作用仍存在争议。我们的研究表明，单次系统性野生型（WT）造血干细胞和祖细胞（HSPC）移植可挽救 5xFAD 小鼠的 AD 表型，且移植可能预防小胶质细胞激活。事实上，与未治疗的 5xFAD 小鼠和接受 5xFAD HSPC 移植的小鼠相比，WT HSPC 移植的 5xFAD 小鼠的记忆丧失和神经认知障碍以及海马体和皮质中的β-淀粉样斑块减少得到完全预防，且神经炎症也显著减少。转录组分析显示，WT HSPC 移植的 5xFAD 小鼠的大脑皮层中与“疾病相关小胶质细胞”和海马体中与“神经退行性变相关的内皮细胞”相关的基因表达显著下降。这项工作表明，HSPC 移植有可能预防 AD 相关并发症，是治疗这种疾病的有前途的途径。
